AU8649098A - Phenethylamine derivatives - Google Patents

Abstract

Compounds represented by general formula (1) which are phenethylamine derivatives exhibiting a motilin receptor antagonism etc. and being useful as drugs, wherein A represents an amino acid residue, etc.; R1 represents R6 -CO-, etc.; R2 represents hydrogen, etc.; R3 represents -CO-R7 , etc.; R4 represents alkyl, etc.; R5 represents hydroxy, etc.; R6 represents alkyl, etc ; and R7 represents amino, etc. <CHEM>

Description

SPECIFICATION PHENETHYLAMINE DERIVATIVES TECHNICAL FIELD This invention relates to phenethylamine derivatives 5 that typically function as a motilin receptor antagonist and which are useful as medicines. BACKGROUND ART Motilin, which is one of the gastrointestinal hormones, is a straight-chained peptide consisting of 22 amino acids 10 and is well known to be responsible for regulating the motility of the gastrointestinal tract in animals including human. It has been reported that exogenously administered motilin causes contractions in humans and dogs that are similar to interdigestive migrating contractions, 15 thus promoting gastric emptying (Itoh et al., Scand. J. Gastroenterol., 11, 93-110 (1976); Peeters et al., Gastroenterology 102, 97-101 (1992)). Hence, erythromycin derivatives which are an agonist of motilin are under development as an gastrointestinal tract motor activity 20 enhancer (Satoh et al., J. Pharmacol. Exp. Therap., 271, 574-579 (1994); Lartey et al., J. Med. Chem., 38, 1793-1798 (1995); Drug of the Future, 19, 910-912 (1994)). Peptide and polypeptide derivatives have been reported as antagonists of motilin receptors (Depoortere et al., Eur. 25 J. Pharmacol., 286, 241-247 (1995); Poitras et al., Biochem. Biophys. Res. Commun., 205, 449-454 (1994); Takanashi et al., J. Pharmacol. Exp. Ther., 273, 624-628 (1995)). These derivatives are used as a pharmacological tool in the study - 1of the action of motilin on the motility of the gastrointestinal tract and in the research and development of medicines in the field of the art contemplated by the invention. 5 Motilin receptors had been known to exist principally in the duodenum but recently it has been shown that they also exist in the large intestine, or the lower part of the gastrointestinal tract (William et al., Am. J. Physiol., 262, G50-G55 (1992)), and this indicates the possibility that 10 motilin is involved not only in the motility of the upper part of the gastrointestinal tract but also in the motility of its lower part. Reports have also been made of the cases of hypermotilinemia in patients with irritable bowel syndrome 15 who were manifesting diarrhea and in patients with irritable bowel syndrome who were under stress (Preston et al., Gut, 26, 1059-1064 (1985); Fukudo et al., Tohoku J. Exp. Med., 151, 373-385 (1987)) and this suggests the possibility that increased blood motilin levels are involved in the disease. 20 Other diseases that have been reported to involve hypermotilinemia include crohn's disease, ulcerative colitis, pancreatitis, diabetes mellitus, obesity, malabsorption syndrome, bacterial diarrhea, atrophic gastritis and postgastroenterectomy syndrome. The antagonists of motilin 25 receptors have the potential to ameliorate irritable bowel syndrome and other diseased states accompanied by increased blood motilin levels. DISCLOSURE OF INVENTION -2- An object of the invention is to provide phenethylamine derivatives that function as an antagonist of motilin receptors and which are useful as medicines. The present inventors conducted repeated intensive 5 studies in an attempt to develop compounds having an outstanding motilin receptor antagonistic action. As a result, they found that phenethylamine derivatives represented by the general formula (1) were an excellent antagonist of motilin receptors. The present invention has 10 been accomplished on the basis of this finding. Thus, the present invention provides compounds represented by the general formula (1), hydrates thereof or pharmaceutically acceptable salts thereof: R5 15 R RI-A, Ra N R 3 (wherein A is an amino acid residue or an Na-substituted 20 amino acid residue, provided that A binds with -NR 2 - to form an amide; R, is an optionally substituted straight-chained or branched alkyl group having 2 - 7 carbon atoms, an optionally substituted straight-chained or branched alkenyl 25 group having 3 - 8 carbon atoms, or an optionally substituted straight-chained or branched alkynyl group having 3 - 8 carbon atoms;

R

2 is a hydrogen atom or an optionally substituted -3 straight-chained or branched alkyl group having 1 - 3 carbon atoms;

R

3 is -CO-R 7 , an optionally substituted straight chained or branched alkyl group having 1 - 5 carbon atoms, 5 an optionally substituted straight-chained or branched alkenyl group having 2 - 5 carbon atoms or an optionally substituted straight-chained or branched alkynyl group having 2 - 5 carbon atoms;

R

4 is a hydrogen atom, a straight-chained or branched 10 alkyl group having 1 - 6 carbon atoms, a straight-chained or branched alkenyl group having 2 - 6 carbon atoms, a straight-chained or branched alkynyl group having 2 - 6 carbon atoms, or the general formula (2): 15

R

15 R16 (2) R17 R. is a hydrogen atom or -OR,; 20 R 6 is an optionally substituted straight-chained or branched alkyl group having 1 - 6 carbon atoms, an optionally substituted straight-chained or branched alkenyl group having 2 - 7 carbon atoms, an optionally substituted alkynyl group having 2 - 7 carbon atoms, a cycloalkyl group 25 having 3 - 7 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, an optionally substituted aromatic ring having 6 - 12 carbon atoms, an optionally substituted saturated or unsaturated heterocyclic ring RA

-

having 3 - 12 carbon atoms, -N(R,)Rl 0 or -OR,,;

R

7 is a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon atoms, a cycloalkyl group having 3 - 7 carbon atoms, 5 -N(R 2

)R.

3 or -OR 14 ;

R

8 is a hydrogen atom or a straight-chained alkyl group having 1 - 4 carbon atoms;

R

9 and R 10 , which may be the same or different, each represent a hydrogen atom, an optionally substituted 10 straight-chained or branched alkyl group having 1 - 5 carbon atoms, an optionally substituted straight-chained or branched alkenyl group having 2 - 6 carbon atoms, an opotionally substituted straight-chained or branched alkynyl group having 2 - 6 carbon atoms, a cycloalkyl group having 3 15 - 6 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, or an optionally substituted aromatic ring having 6 - 12 carbon atoms;

R

11 is an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon atoms, an 20 optionally substituted straight-chained branched alkenyl group having 2 - 6 carbon atoms, an optionally substituted straight-chained or branched alkynyl group having 2 - 6 carbon atoms, a cycloalkyl group having 3 - 6 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, 25 or an optionally substituted aromatic ring having 6 - 12 carbon atoms;

R

12 and R.

3 , which may be the same or different, each represent a hydrogen atom, a straight-chained or branched -5 alkyl group having 1 - 4 carbon atoms or a cycloalkyl group having 3 - 7 carbon atoms;

R

14 is a hydrogen atom, a straight-chained or branched alkyl group having 1 - 6 carbon atoms, or a cycloalkyl group 5 having 3 - 7 carbon atoms; R,, is a hydrogen atom or a methyl group;

R.

6 and R 17 , when taken together, represent a cycloalkyl or cycloalkenyl group having 3 - 7 carbon atoms). The present invention also provides a medicine 10 containing a compound of the general formula (1) as an active ingredient. Further, the invention provides a motilin receptor antagonist containing said compound. The invention also provides a gastrointestinal motility suppressor containing said compound as an active ingredient. 15 Further, the invention provides a therapeutic of hypermotilinemia containing said compound as an active ingredient. In the definition of the compounds represented by the general formula (1), the amino acid residue as A may be of 20 any types commonly known in the art, as exemplified by a-, P- and y-amino acid residues. Specific examples include glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tyrosine (Tyr), tryptophan (trp), histidine (His), asparagine (Asn), 25 glutamine (Gln), aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), serine (Ser), threonine (Thr), methionine (Met), proline (Pro), $-alanine (p-Ala), hydroxyproline (Hyp), citrulline (Cit), ornithine (Orn), phenylglycine 4-6 C'6 (Phg), norvaline (Nva), aminoisobutyric acid (Aib), homophenylalanine (Hph), 2-thienylalanine (Thi), y aminobutyric acid (y-Abu), cyclohexylglycine (Chg), cyclo hexylalanine (Cha), tert-leucine (Tle), aminoadipic acid 5 (Aad), diaminobutyric acid (Dab), homoserine (Hse), amino butyric acid (Abu), 2-aminobenzoic acid (2-Abz), thioproline (Thz), 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (Tiq), 1-aminocyclopropanecarboxylic acid (Apc), 1-amino 10 cyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid and 1-aminocyclohexanecarboxylic acid (Ahc); preferred are valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), phenylglycine (Phg), hydroxyproline (Hyp), homophenylalanine 15 (Hph), cyclohexylglycine (Chg), cyclohexylalanine (Cha), tert-leucine (Tle) and 2-thienylalanine; more preferred are valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), phenylglycine (Phg) and cyclohexylalanine (Cha). These amino acid residues and Na-amino acid residues may be 20 any of L-, D- and DL-forms, with the L-form being preferred. The Na-substituted amino acid residue as A is such that a hydrogen atom in the amino group in the a-position of any one of the above-mentioned a-amino acid residues is substituted. Examples of the substituent on the Na 25 substituted amino acid residue include a straight-chained or branched alkyl group having 1 - 3 carbon atoms that may be substituted by a benzene ring and the like, and a methyl group is preferred. -7- Examples of the a-amino acid residue in the Na substituted amino acid residue as A include the amino acids mentioned above; preferred are Val, Leu, Ile, Phe, Tyr, Trp, Phg, Chg, Cha, Tle and Thi; more preferred are Val, Leu, Ile, 5 Phe, Phg and Cha. Examples of the Na-substituted amino acid residue as A include N-methylvaline (N-Me-Val), N-methylleucine (N-Me Leu), N-methylisoleucine (N-Me-Ile), N-methylphenylalanine (N-Me-Phe), N-methyltyrosine (N-Me-Tyr), N-methyltryptophan 10 (N-Me-Trp), N-methylphenylglycine (N-Me-Phg), N-methyl cyclohexylglycine (N-Me-Chg), N-methylcyclohexylalanine

(N

Me-Cha), N-methyl-tert-leucine (N-Me-Tle), and N-methyl-2 thienylalanine (N-Me-Thi); preferred are N-Me-Val, N-Me-Leu, N-Me-Ile, N-Me-Phe, N-Me-Phg and N-Me-Cha; more preferred as 15 N-Me-Val and N-Me-Phg. The definition of R 1 includes R 6 -CO-, in which R 6 may be an optionally substituted straight-chained or branched alkyl group having 1 - 6 carbon atoms, preferably a straight-chained or branched alkyl group having 1 - 5 carbon 20 atoms, more preferably a straight-chained or branched alkyl group having 2 - 3 carbon atoms, with an ethyl group being particularly preferred. In the definition of R 6 -CO- as R 1 , R 6 may be an optionally substituted straight-chained or branched alkenyl 25 group having 2 - 7 carbon atoms, preferably a straight chained or branched alkenyl group having 4 - 6 carbon atoms. In the definition of R 6 -CO- as R 1 , R 6 may be an RA4 1 optionally substituted straight-chained or branched alkynyl -8group having 2 - 7 carbon atoms, preferably a straight chained or branched alkynyl group having 4 - 6 carbon atoms. In the definition of R 6 -CO- as R 1 , R 6 may be an optionally substituted straight-chained or branched alkyl 5 group having 1 - 6 carbon atoms, an optionally substituted straight-chained or branched alkenyl group having 2 - 7 carbon atoms or an optionally substituted straight-chained or branched alkynyl group having 2 - 7 carbon atoms, and exemplary substituents include an amino group, a methylamino 10 group, an ethylamino group, a dimethylamino group, a trimethylammonium group, a hydroxyl group, a carboxyl group, an aminocarbonyl group, an aminocarbonylamino group, a pyridylthio group, a methylthio group, a phenyl group, a 3 indolyl group, a 4-hydroxyphenyl group, a 2-thienyl group, a 15 2-furyl group, a 3-imidazolyl group and a cyclohexyl group; preferred are an amino group, a methylamino group, a phenyl group, a 3-indolyl group, a 4-hydroxyphenyl group, a 2 thienyl group, a 2-furyl group and a cyclohexyl group; more preferred are an amino group and a phenyl group. The above 20 mentioned alkyl, alkenyl and alkynyl groups may have one or more of the above-mentioned substituents, which may be the same or different. In the definition of R 6 -CO- as R 1 , R 6 may be an optionally substituted straight-chained or branched alkyl 25 group having 1 - 6 carbon atoms, preferably a straight chained or branched alkyl group of 2 - 3 carbon atoms having one or more of the above-mentioned substituents, which may be the same or different; notably, a 1-amino-2-phenylethyl -9 group, a 1-methylamino-2-phenylethyl group, a 1-amino-2-(3 indolyl)ethyl group, a 1-amino-2-(4-hydroxy)phenylethyl group, a 1-amino-2-(2-thienyl)ethyl group, a 1-amino-2-(2 furyl)ethyl group, a 1-amino-2-cyclohexylethyl group and a 5 2-phenylpropyl group are preferred, and a 1-amino-2 phenylethyl group is particularly preferred. In the definition of RI-CO- as R 1 , R 6 may be an optionally substituted straight-chained or branched alkenyl group having 2 - 7 carbon atoms, preferably a straight 10 chained or branched alkenyl group of 4 - 6 carbon atoms having one or more of the above-mentioned substituents. In the definition of R 6 -CO- as R 1 , R 6 may be an optionally substituted straight-chained or branched alkynyl group having 2 - 7 carbon atoms, preferably a straight 15 chained or branched alkynyl group of 4 - 6 carbon atoms having one or more of the above-mentioned substituents. In the definition of R 6 -CO- as R 1 , R 6 may be a cycloalkyl group having 3 - 7 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, and examples of 20 the heterocyclic ring include aliphatic or aromatic 5- or 6 membered rings containing one or two hetero atoms selected from among 0, N and S; specific examples include pyridine, pyrazine, furan, thiophene, pyrrole and imidazole. In the definition of R 6 -CO- as R 1 , R 6 may be a 25 cycloalkyl group having 3 - 7 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, preferably a cycloalkyl group having 3 - 7 carbon atoms that is fused to a benzene ring, with a 1-benzocyclobutyl group being -10 particularly preferred. In the definition of R 6 -CO- as R 1 , R 6 may be an optionally substituted aromatic ring having 6 - 12 carbon atoms, as exemplified by a benzene ring and a naphthalene 5 ring. In the definition of R 6 -CO- as R 1 , R 6 may be an optionally substituted aromatic ring having 6 - 12 carbon atoms and exemplary substituents include a hydroxyl group, a methoxy group, a phenoxy group, a benzyloxy group, a tert 10 butyloxy group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a carboxyl group, and a methoxycarbonyl group. The aromatic ring may have one or more of the above-mentioned substituents, which may be the same or different. 15 In the definition of R 6 -CO- as R 1 , R 6 may be an optionally substituted saturated or unsaturated heterocyclic ring having 3 - 12 carbon atoms, as exemplified by aliphatic or aromatic 5- to 10-membered monocyclic or fused rings containing one or more hetero atoms selected from among 0, N 20 and S; specific examples include pyrrolidine, piperidine, piperazine, tetrahydroisoquinoline, pyridine, pyrazine, furan, thiophene, pyrrole, imidazole, quinoline, indole, benzimidazole and benzofuran. In the definition of R 6 -CO- as R 1 , R 6 may be an 25 optionally substituted saturated or unsaturated heterocyclic ring having 3 - 12 carbon atoms and exemplary substituents include a hydroxyl group, a methoxy group, a phenoxy group, a benzyloxy group, a tert-butyloxy group, an amino group, a - 11 methylamino group, a dimethylamino group, an ethylamino group, a carboxyl group and a methoxycarbonyl group. The heterocyclic ring may have one or more of the above mentioned substituents, which may be the same or different. 5 In the definition of R 6 -CO- as R 1 , R 6 may be an optionally substituted saturated or unsaturated heterocyclic ring having 3 - 12 carbon atoms, as exemplified by the above-mentioned heterocyclic rings that may have one or more of the above-mentioned substituents, which may be the same 10 or different. In the definition of R 6 -CO- as R 1 , R 6 may be -N(R,)RjO, in which R 9 and R 10 may each represent an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon atoms, preferably a straight-chained or 15 branched alkyl group having 1 - 4 carbon atoms, more preferably a straight-chained alkyl group having 1 - 2 carbon atoms, with a methyl group being particularly preferred. In the definition of R 6 -CO- as R 1 , R 6 may be -N(R,)R 10 , 20 in which R 9 and R 10 may each represent an optionally substituted straight-chained or branched alkenyl group having 2 - 6 carbon atoms, preferably a straight-chained or branched alkenyl group having 3 - 6 carbon atoms. In the definition of R 6 -CO- as R 1 , R 6 may be -N(R,)Rjo, 25 in which R 9 and R 10 may each represent an optionally substituted straight-chained or branched alkynyl group having 2 - 6 carbon atoms, preferably a straight-chained or RA branched alkynyl group having 3 - 6 carbon atoms. - 12 - In the definition of R 6 -CO- as R 1 , R 6 may be -N(R,)R 0 , in which R 9 and R 10 each represent an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon atoms, an optionally substituted straight-chained or 5 branched alkenyl group having 2 - 6 carbon atoms or an optionally substituted straight-chained or branched alkynyl group having 2 - 6 carbon atoms. Exemplary substituents include an amino group, a hydroxyl group, a carboxyl group, an aminocarbonyl group, an aminocarbonylamino group, a 10 pyridylthio group, a methylthio group, a phenyl group, a 3 indolyl group, a 4-hydroxyphenyl group, a thienyl group, a 2-furyl group, a 3-imidazolyl group, and a cyclohexyl group; preferred are an amino group, a phenyl group, a 3-indolyl group, a 4-hydroxyphenyl group, a 2-thienyl group, a 2-furyl 15 group and a cyclohexyl group; more preferred is a phenyl group. These alkyl, alkenyl and alkynyl groups may have one or more of the above-mentioned substituents, which may be the same or different. In the definition of R 6 -CO- as R 1 , R 6 may be -N(R,)R 0 , 20 in which R 9 and R 1 , may each represent an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon atoms, preferably a methyl group having one or more of the above-mentioned substituents, more preferably a benzyl group, a 3-indolylmethyl group, a p-hydroxybenzyl 25 group, a 2-thienylmethyl group, a 2-furylmethyl group or a cyclohexylmethyl group, with a benzyl group being particularly preferred. In the definition of R 6 -CO- as R 1 , R. may be -N(R,)R3 0 , - 13 in which R 9 and RIO may each represent an optionally substituted straight-chained or branched alkenyl group having 2 - 6 carbon atoms, preferably a straight-chained or branched alkenyl group having 3 - 6 carbon atoms. 5 In the definition of R 6 -CO- as R 1 , R 6 may be -N(R,)R 0 , in which R 9 and RIO may each represent an optionally substituted straight-chained or branched alkynyl group having 2 - 6 carbon atoms, preferably a straight-chained or branched alkynyl group having 3 - 6 carbon atoms. 10 In the definition of R 6 -CO- as R 1 , R 6 may be -N(R,)Rlo, in which R 9 and RIO may each represent a cycloalkyl group having 3 - 6 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, and the heterocyclic ring may be exemplified by aliphatic or aromatic 5- or 6-membered 15 ring containing one or two hetero atoms selected from among 0, N and S; specific examples of such heterocyclic ring include pyridine, pyrazine, furan, thiophene, pyrrole and imidazole. In the definition of R 6 -CO- as R 1 , R 6 may be -N(R,)Rjo, 20 in which R 9 and RIO may each represent a cycloalkyl group having 3 - 6 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, and such cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. 25 In the definition of R 6 -CO- as R 1 , R. may be -N(R,)Rjo, in which R 9 and RIO may each represent a cycloalkyl group having 3 - 6 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, as exemplified by a cycloalkyl R14 - 14 */ group having 3 - 6 carbon atoms that may be fused to a benzene ring or one or more of the heterocyclic rings mentioned above. In the definition of R 6 -CO- as R 1 , R 6 may be -N(R,)RjO, 5 in which R 9 and RIO may each represent an optionally substituted aromatic ring having 6 - 12 carbon atoms, as exemplified by a benzene ring and a naphthalene ring. In the definition of R 6 -CO- as R 1 , R 6 may be -N(R,)RI., in which R 9 and RIO may each represent an optionally 10 substituted aromatic ring having 6 - 12 carbon atoms, and exemplary substituents include a hydroxyl group, a methoxy group, a phenoxy group, a benzyloxy group, a tert-butyloxy group, an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a carboxyl group and a 15 methoxycarbonyl group. The aromatic ring may have one or more of these substituents, which may be the same or different. While R 9 and RIO in -N(R,)Rl, in R 6 in R 6 -CO- as R, has the definitions set forth above, -N(R,)Rlo is preferably a 20 benzylamino group or a benzylmethylamino group. In the definition of R 6 -CO- as R 1 , R 6 may be -OR, 1 , in which R 11 may be an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon atoms, preferably a straight-chained or branched alkyl group having 25 1 - 4 carbon atoms, more preferably a straight-chained alkyl group having 1 - 2 carbon atoms, with a methyl group being particularly preferred. In the definition of R 6 -CO- as R 1 , R, may be -OR,,, in RA1 - 15 which R 11 may be an optionally substituted straight-chained or branched alkenyl group having 2 - 6 carbon atoms, preferably a straight-chained or branched alkenyl group having 3 - 6 carbon atoms. 5 In the definition of R 6 -CO- as R 1 , R 6 may be -OR3 1 , in which R 1 , may be an optionally substituted straight-chained or branched alkynyl group having 2 - 6 carbon atoms, preferably a straight-chained or branched alkynyl group having 3 - 6 carbon atoms. 10 In the definition of R 6 -CO- as R 1 , R 6 may be -OR 1 , in which R 11 is an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon atoms, an optionally substituted straight-chained or branched alkenyl group having 2 - 6 carbon atoms or an optionally substituted 15 straight-chained or branched alkynyl group having 2 - 6 carbon atoms. Exemplary substituents include an amino group, a hydroxyl group, a carboxyl group, an aminocarbonyl group, an aminocarbonylamino group, a pyridylthio group, a methylthio group, a phenyl group, a 3-indolyl group, a 4 20 hydroxyphenyl group, a 2-thienyl group, a 2-furyl group, a 3-imidazolyl group and a cyclohexyl group; preferred are an amino group, a phenyl group, a 3-indolyl group, a 4 hydroxyphenyl group, a 2-thienyl group, a 2-furyl group and a cyclohexyl group; more preferred is a phenyl group. The 25 above-mentioned alkyl, alkenyl and alkynyl groups may have one or more of the above-mentioned substituents, which may be the same or different. In the definition of R 6 -CO- as R 1 , R 6 may be -OR, - 16 in which R 11 may be an optionally substituted straight chained or branched alkyl group having 1 - 5 carbon atoms, preferably a methyl group having one or more of the above-mentioned substituents, more preferably a benzyl 5 group, a 3-indolylmethyl group, a p-hydroxybenzyl group, a 2-thienylmethyl group, a 2-furylmethyl group, and a cyclohexylmethyl group, with a benzyl group being particularly preferred. In the definition of R 6 -CO- as R 1 , R 6 may be -OR,,, in 10 which R,, may be an optionally substituted straight-chained or branched alkenyl group having 2 - 6 carbon atoms, preferably a straight-chained or branched alkenyl group having 3 - 6 carbon atoms. In the definition of R 6 -CO- as R3, R 6 may be -OR, 1 , in 15 which R,, may be an optionally substituted straight-chained or branched alkynyl group having 2 - 6 carbon atoms, preferably a straight-chained or branched alkynyl group having 3 - 6 carbon atoms. In the definition of R 6 -CO- as R 1 , R 6 may be -OR 11 , 20 in which R 11 may be a cycloalkyl group having 3 - 6 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, and the heterocyclic ring may be exemplified by an aliphatic or aromatic 5- or 6-membered ring containing one or two hetero atoms selected from among 0, N and S. 25 Specific examples of such heterocyclic ring include pyridine, pyrazine, furan, thiophene, pyrrole and imidazole. In the definition of R 6 -CO- as R 1 , R 6 may be -OR 11 , in which R 11 may be a cycloalkyl group having 3 - 6 carbon -17 * atoms that may be fused to a benzene ring or a heterocyclic ring, and the cycloalkyl group is a cyclopropyl group, a cyclobutyl group or a cyclopentyl group. In the definition of R 6 -CO- as R 1 , R 6 may be -OR,,, in 5 which R 11 may be a cycloalkyl group having 3 - 6 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, as exemplified by a cycloalkyl group having 3 - 6 carbon atoms that may be fused to a benzene ring or one or more of the above-mentioned heterocyclic rings. 10 In the definition of R 6 -CO- as R 1 , R 6 may be -OR 1 , in which R,, may be an optionally substituted aromatic ring having 6 - 12 carbon atoms, as exemplified by a benzene ring and a naphthalene ring. In the definition of R 6 -CO- as R 1 , R 6 may be -OR, 1 , in 15 which R 1 , may be an optionally substituted aromatic ring having 6 - 12 carbon atoms, and exemplary substituents include a hydroxyl group, a methoxy group, a phenoxy group, a benzyloxy group, a tert-butyloxy group, an amino group, a methylamino group, a dimethylamino group, an ethylamino 20 group, a carboxyl group, and a methoxycarbonyl group. The aromatic ring may have one or more of the above-mentioned substituents, which may be the same or different. In the definition of RI-CO- as R 1 , R 6 may be -OR 1 , in which R,, may be an optionally substituted aromatic ring 25 having 6 - 12 carbon atoms, as exemplified by a benzene ring and a naphthalene ring that optionally have one or more of the above-mentioned substituents, which may be the same or different. -18- While R3 1 in -OR 11 in R 6 in R 6 -C0- as R 1 has the definitions set forth above, -OR, is preferably a benzyloxy group. While R 6 in R 6 -CO- as R 1 has the definitions set 5 forth above, preferred examples of R 6 include a 1-amino-2 phenylethyl group, a 1-methylamino-2-phenylethyl group, a 1-amino-2-(3-indolyl)ethyl group, a 1-amino-2-( 4 hydroxy)phenylethyl group, a 1-amino-2-(2-thienyl)ethyl group, a 1-amino-2-(2-furyl)ethyl group, a 1-amino-2 10 cyclohexylethyl group, a 2-phenylpropyl group, a 1 benzocyclobutyl group, a benzylamino group and a benzyloxy group, with a 1-amino-2-phenhylethyl group being particularly prefered. In its definition,

R

1 may be an optionally substituted 15 straight-chained or branched alkyl group having 2 - 7 carbon atoms, preferably a straight-chained or branched alkyl group having 3 - 4 carbon atoms, with a propyl group being particularly preferred. In its definition, R, may be an optionally substituted 20 straight-chained or branched alkenyl group having 3 - 8 carbon atoms, preferably a straight-chained or branched alkenyl group having 4 - 8 carbon atoms, more preferably a straight-chained or branched alkenyl group having 5 - 7 carbon atoms. 25 In its definition,

R

1 may be an optionally substituted straight-chained or branched alkynyl group having 3 - 8 carbon atoms, preferably a straight-chained or branched alkynyl group having 3 - 7 carbon atoms, more preferably a 4, 19 straight-chained or branched alkynyl group having 5 - 7 carbon atoms. In its definition, R 1 may be an optionally substituted straight-chained or branched alkyl group having 2 - 7 carbon 5 atoms, an optionally substituted straight-chained or branched alkenyl group having 3 - 8 carbon atoms, or an optionally substituted straight-chained or branched alkynyl group having 3 - 8 carbon atoms. Exemplary substituents include an amino group, a methylamino group, an ethylamino 10 group, a dimethylamino group, a hydroxyl group, a carboxyl group, an aminocarbonyl group, an aminocarbonylamino group, a pyridylthio group, a methylthio group, a phenyl group, a 3-indolyl group, a 4-hydroxyphenyl group, a 2-thienyl group, a 2-furyl group, a 3-imidazolyl group, and a cyclohexyl 15 group; preferred are an amino group, a phenyl group, a 3 indolyl group, a 4-hydroxyphenyl group, a 2-thienyl group, a 2-furyl group, and a cyclohexyl group; more preferred are an amino group and a phenyl group. The above-described alkyl, alkenyl and alkynyl groups may have one or more of the 20 above-mentioned substituents, which may be the same or branched. The optionally substituted straight-chained or branched alkyl group as R 1 which has 2 - 7 carbon atoms is preferably a straight-chained or branched alkyl group of 3 25 4 carbon atoms that has one or more of the above-mentioned substituents, which may be the same or different. Preferred examples include a 2-amino-3-phenylpropyl group, a 2-amino-3-(3-indolyl)propyl group, a 2-amino-3-(4 RA - 20 hydroxy)phenylpropyl group, a 2-amino-3-(2-thienyl)propyl group, a 2-amino-3-(2-furyl)propyl group, a 2-amino-3 cyclohexylpropyl group, and a 3-phenylbutyl group, with a 2-amino-3-phenyhlpropyl group being particularly preferred. 5 The optionally substituted straight-chained or branched alkenyl group as R 1 which has 3 - 8 carbon atoms is preferably a straight-chained or branched alkenyl group of 4 - 8 carbon atoms that has one or more of the above-mentioned substituents. 10 The optionally substituted straight-chained or branched alkynyl groups as R, which has 2 - 7 carbon atoms is preferably a straight-chained or branched alkynyl group of 3 - 7 carbon atoms that has one or more of the above mentioned substituents. 15 While R, has the definitions set forth above, it is preferably a phenylalaninoyl group, an N-Me phenylalaninoyl group, a P-(3-indolyl)alaninoyl group, a tyrosinoyl group, a @-(2-thienyl)alaninoyl group, a P-(2-furyl)alaninoyl group, a P-cyclohexylalaninoyl group, a 3-phenylbutyryl group, a 1 20 benzocyclobutylcarbonyl group, a benzylaminocarbonyl group or a benzyloxycarbonyl group, with a phenylalaninoyl group being particularly preferred. In its definition,

R

2 may be an optionally substituted straight-chained or branched alkyl group having 1 - 3 carbon 25 atoms, as exemplified by a methyl group, an ethyl group, a propyl group and an isopropyl group; preferred are a methyl group and an ethyl group, and a methyl group is more preferred. - 21 - Exemplary substituents for the optionally substituted straight-chained or branched alkyl group as R 2 which has 1 - 3 carbon atoms include a phenyl group, a hydroxyl group, an amino group and a carboxyl group. The alkyl group may 5 optionally have one or more of these substituents, which may be the same or different. The optionally substituted straight-chained or branched alkyl group as R 2 which has 1 - 3 carbon atoms is preferably a methyl group. 10 While R2 has the definitions set forth above, it is preferably a hydrogen atom or a methyl group. In its definition, R3 may be -CO-R 7 , in which R 7 may be an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon atoms, preferably a straight 15 chained or branched alkyl group having 1 - 3 carbon atoms. In its definition, R 3 may be -CO-R 7 , in which R 7 may be an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon atoms, and exemplary substituents include a halogen, an amino group, a hydroxyl group and an 20 alkoxy group, with halogen being preferred. In its definition, R 3 may be -CO-R 7 , in which R7 may be an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon atoms, preferably a straight chained or branched alkyl group having one or more of the 25 above-mentioned substituents which are the same as each other, more preferably a fluoromethyl group or a chloromethyl group. In its definition, R 3 may be -CO-R 7 , in which R7 may be -22 a cycloalkyl group having 3 - 7 carbon atoms, preferably a cycloalkyl group having 3 - 5 carbon atoms. In its definition, R 3 may be -CO-R 7 , in which R 7 may be

N(R,,)R

13 , wherein R 12 and R 13 may be a straight-chained or 5 branched alkyl group having 1 - 4 carbon atoms, preferably a straight-chained alkyl group having 1 - 2 carbon atoms, more preferably a methyl group. In its definition, R 3 may be -CO-R 7 , in which R 7 may be

N(R

12

)R

13 , wherein R 12 and R 13 may be a cycloalkyl group having 10 3 - 7 carbon atoms, preferably a cycloalkyl group having 3 5 carbon atoms. In its definition, R 3 may be -CO-R 7 , in which R, may be

N(R

12 )R3, wherein R2 and R1, which may be the same or different, are preferably a hydrogen atom or a methyl group. 15 While R 12 and R 13 in -N(Rl 2 )Rl 3 in R 7 in -CO-R 7 as R 3 have the definitions set forth above, -N(R,)Rl, is preferably an amino group or a methylamino group. In its definition, R 3 may be -CO-R 7 , in which R 7 may be

-OR

14 , wherein R.

4 may be a straight-chained or branched 20 alkyl group having 1 - 6 carbon atoms, preferably a straight-chained alkyl group having 1 - 2 carbon atoms, more preferably a methyl group. In its definition, R 3 may be -CO-R 7 , in which R 7 may be

-OR

4 , wherein R 14 may be a cycloalkyl group having 3 - 7 25 carbon atoms, which is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group, with a cyclopropyl group being preferred. RA4, While R 14 in -OR 14 in R 7 in -CO-R 7 as R 3 has the - 23 wJ definitions set forth above, -OR 14 is preferably a hydroxyl group or a methoxy group. While -CO-R., as R 3 has the definitions set forth above, it is preferably an amido group or an N-methylamido group. 5 In its definition, R 3 may be an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon atoms, preferably a straight-chained or branched alkyl group having 1 - 3 carbon atoms, with a methyl group being particularly preferred. 10 In its definition, R 3 may be an optionally substituted straight-chained or branched alkenyl group having 2 - 5 carbon atoms, preferably a straight-chained or branched alkenyl group having 2 - 3 carbon atoms. In its definition, R 3 may be an optionally substituted 15 straight-chained or branched alkynyl group having 2 - 5 carbon atoms, preferably a straight-chained alkynyl group having 2 - 3 carbon atoms. In its definition, R 3 may be an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon 20 atoms, an optionally substituted straight-chained or branched alkenyl group having 2 - 5 carbon atoms or an optionally substituted straight-chained or branched alkynyl group having 2 - 5 carbon atoms. Exemplary substituents include an amino group, an alkylamino group, a hydroxyl 25 group, an alkoxy group, a carboxyl group, a halogen, etc., with an amino group being particularly preferred. The above-described alkyl, alkenyl and alkynyl groups may optionally have one or more of the above-mentioned -24 substituents, which may be the same or different. The optionally substituted straight-chained or branched alkyl group as R3 which has 1 - 5 carbon atoms is preferably a methyl group and an aminomethyl group. 5 While R 3 has the definitions set forth above, it is preferably an amido group, an N-methylamido group, a methyl group or an aminomethyl group, with an amido group and a methyl group being particularly preferred. In its definition, R 4 may be a straight-chained or 10 branched alkyl group having 1 - 6 carbon atoms, preferably a straight-chained or branched alkyl group having 2 - 5 carbon atoms, more preferably a branched alkyl group having 3 - 5 carbon atoms, with a tert-butyl group being particularly preferred. 15 In its definition, R 4 may be a straight-chained or branched alkenyl group having 2 - 6 carbon atoms, preferably a straight-chained or branched alkenyl group having 3 - 5 carbon atoms, more preferably a branched alkenyl group having 3 - 5 carbon atoms. 20 In its definition, R 4 may be a straight-chained or branched alkynyl group having 2 - 6 carbon atoms, preferably a straight-chained or branched alkynyl group having 3 - 5 carbon atoms, more preferably a branched alkynyl group having 3 - 5 carbon atoms. 25 In its definition, R 4 may have the general formula (2), in which R 1 . is preferably a methyl group. In the general formula (2) as R 4 , R 16 and R 1 7 when taken together may form a cycloalkyl group having 3 - 7 carbon -25 atoms, which is preferably a cycloalkyl group having 3 - 5 carbon atoms. In the general formula (2) as R 4 , R 1 . and R.7 when taken together may alternatively form a cycloalkenyl group having 5 3 - 7 carbon atoms, which is preferably a cycloalkenyl group having 4 - 6 carbon atoms. The preferred examples of R 4 are an isopropyl group, a tert-butyl group, a 1,1-dimethylpropyl group, and a 1,1 dimethyl-2-propenyl group, with a tert-butyl group being 10 particularly preferred. In its definition, R. may represent -OR 12 , in which R 12 may be a straight-chained alkyl group having 1 - 4 carbon atoms, preferably a methyl group and an ethyl group, more preferably a methyl group. 15 The preferred examples of R. are a hydroxyl group and a methoxy group, with a hydroxyl group being particularly preferred. The preferred examples of the compound represented by the general formula (1): 20 R5 R4 (1) R-A, R 4 RA.N R 3

R

2 25 (where R 1 , R 2 , R 3 , R 4 and R 5 have the same meanings as defined above) are: Phe-Hyp-Tyr(3-tBu)-NH 2 , Phe-Thz-Tyr(3-tBu)-NH 2 , Phe-Pro-Tyr(3-tBu)-NH2 , Phe-Phg-Tyr(3-tBu)-NH2 , Phe-Phg Phe(3-tBu-4-methoxy)-NH2 , Phe-N-Me-Phg-Tyr(3-tBu)-NH2, Phe -26 - N-Me-D-Phg-Tyr(3-tBu)-NH 2 , Phe-Phe-Tyr(3-tBu)-NH 2 , Phe-Cha Tyr(3-tBu)-NH 2 , Phe-Chg-Tyr(3-tBu)-NH 2 , Phe-Tle-Tyr(3-tBu)

NH

2 , Phe-Val-Tyr(3-tBu)-NH 2 , Phe-Leu-Tyr(3-tBu)-NH 2 , Phe-Tyr Tyr(3-tBu)-NH 2 , Phe-Hph-Tyr(3-tBu)-NH 2 , Phe-Thi-Tyr(3-tBu) 5 NH 2 , Phe-Ile-Tyr(3-tBu)-NH 2 , Phe-Thr-Tyr(3-tBu)-NH 2 , Phe-Trp Tyr(3-tBu)-NH 2 , Tyr-Phg-Tyr(3-tBu)-NH 2 , Phg-Phg-Tyr(3-tBu)

NH

2 , Trp-Phg-Tyr(3-tBu)-NH 2 , Cha-Phg-Tyr(3-tBu)-NH 2 , Hph-Phg Tyr(3-tBu)-NH 2 , N- (a-methylhydrocinnamyl) -Phg-Tyr(3-tBu) -NH 2 , Phe-N-Me-Val-Tyr(3-tBu)-NH 2 , N-(a-methylhydrocinnamyl)-N-Me 10 D-Phg-Tyr(3-tBu)-NH 2 , Phe-Val-N-Me-Tyr(3-tBu)-NH 2 , Phe-Phg Tyr(3-tBu)-NHMe, Phg-Phg-Tyr(3-tBu)-OH, N-(3-phenylbutyryl) Phg-Tyr(3-tBu)-NH 2 , N-(benzylaminocarbonyl)-N-Me-D-Phe Tyr(3-tBu)-NH 2 , N-(benzyloxycarbonyl)-Phg-Tyr(3-tBu) -NH2, N (benzyloxycarbonyl) -N-Me-Val-Tyr(3-tBu) -NH 2 , N-(S)-3 15 phenylbutyryl-Phg-Tyr(3-tBu)-NH 2 , N-((R)-3-phenylbutyryl) Phg-Tyr(3-tBu)-NH 2 , L-a-(3-methyl-2-butenyl)glycinoyl-N-Me Val-Tyr(3-tBu)-NH 2 , a-(4-pentynyl)glycinoyl-N-Me-Val-Tyr(3 tBu)-NH 2 , N-(2-amino-3-phenylpropyl)-Phg-Tyr(3-tBu)-NH 2 , N (2-amino-3-phenylpropyl)-Val-Tyr(3-tBu)-NH 2 , N-[2-(3-tert 20 butyl-4-hydroxyphenyl) -1-methylethyl] -3-methyl-2- (N-methyl N-phenylalaninoylamino)butanamide, and Phe-N-Me-Val-N-Me Tyr(3-tBu)-NH, N-[2-(3-tert-butyl-4-hydroxyphenyl)-1 methylethyl]-3-methyl-2-[N-methyl-N-(N-Me-phenyl alaninoyl)amino]butanamide, and the more preferred examples 25 are: Phe-Phg-Tyr(3-tBu)-NH 2 , Phe-N-Me-D-Phg-Tyr(3-tBu)-NH 2 , Phe-Phe-Tyr(3-tBu)-NH 2 , Phe-Cha-Tyr(3-tBu)-NH 2 , Phe-Val Tyr(3-tBu)-NH 2 , Phe-Leu-Tyr(3-tBu)-NH 2 , Phe-Tyr-Tyr(3-tBu)

NH

2 , Phe-Hph-Tyr(3-tBu)-NH 2 , Phe-Ile-Tyr(3-tBu)-NH 2 , Trp-Phg - 27 - Tyr(3-tBu)-NH 2 , Cha-Phg-Tyr(3-tBu)-NH 2 , Phe-N-Me-Val-Tyr(3 tBu)-NH2' Phe-Val-N-Me-Tyr(3-tBu)-NH2, Phe-Phg-Tyr(3-tBu) NHMe, N-(benzylaminocarbonyl)-N-Me-D-Phe-Tyr(3-tBu)-NH2 , N (S)-3-phenylbutyryl-Phg-Tyr(3-tBu)-NH 2 , N-(2-amino-3 5 phenylpropyl)-Phg-Tyr(3-tBu)-NH 2 , N-(2-amino-3 phenylpropyl)-Val-Tyr(3-tBu)-NH 2 , N-[2-(3-tert-butyl-4 hydroxyphenyl)-1-methylethyl]-3-methyl-2-(N-methyl-N phenylalaninoylamino ) butanamide, Phe-N-Me-Val-N-Me-Tyr (3 tBu)-NH 2 , and N-[2-(3-tert-butyl-4-hydroxyphenyl)-1 10 methylethyl] -3-methyl-2- [N-methyl-N- (N-Me-phenylalaninoyl) amino] butanamide. Salt-forming acids include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids 15 such as acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid, methanesulfonic acid and trifluoroacetic acid. The compounds of the present invention can occur as optical isomers and the respective optical isomers and 20 mixtures thereof are all included within the scope of the invention. The compounds of the invention can also be obtained as hydrates. BEST MODE FOR CARRYING OUT THE INVENTION 25 The compounds represented by the general formula (1) - 28 - R4 () RIAN

R

3

R

2 5 (where A, R 1 , R 2 , R,, R 4 and R 5 respectively have the same meanings as defined above) are amino acid derivatives containing dipeptides or tripeptides and can be produced by either the solid-phase process or the liquid-phase process. 10 In the production by the solid-phase process, an automatic organic synthesizer is typically used but it may be replaced by the manual procedure. Almost all amino acids that compose the compounds of the invention are commercially available and readily 15 purchasable. Those which are not commercially available can be produced by well-known established methods such as the Strecker synthesis, the Bucherer method, the acetamide malonate ester method, and the method of alkylating i glycine ester of which amino group is protected. 20 To produce p-hydroxy-m-substituted phenylalanine esters, tyrosine esters [Tyr-OR 14 (where R.

4 has the same meaning as defined above)] which are either commercially available or obtainable by esterifying tyrosine are subjected to conventional procedures of organic synthesis, 25 for example, the Friedel-Crafts reaction in the presence of proton acids or Lewis acids so that the substituent

R

4 (which is a special case of the foregoing definition where

R

4 is an alkyl group, an alkenyl group or an alkynyl group; -29 W

LCJ

this restriction applies to the present paragraph) is introduced in m-position. Note that the substituent R 4 need not be introduced at this stage but may be introduced at any stage of the production. 5 If the a-amino group in the p-hydroxy-m-substituted phenylalanine ester is 0-alkylated after protection with, for example, a benzyloxycarbonyl, one can obtain a product in which R. in -OR 8 is an alkyl group. If R 5 in the product is a hydrogen atom or an alkoxy group, it is subsequently 10 Na-alkylated to give a product where R 2 is an alkyl group. The hydroxyl group as R 5 is N-alkylated after protection with, for example, a benzyl group or any other group that can be readily removed at a later stage, and then deprotected to give a product where R 2 is an alkyl group and 15 R 5 is a hydroxyl group. Depending on R 3 , a desired structure can be obtained by performing various conversions using ester groups of substituted phenylalanine esters in which the amino acid group and others are appropriately protected. 20 Take, for example, the case where R 3 is an amide; the a-amino group protected substituted phenylalanine ester is directly reacted with the amine HN(R 12

)R

13 or condensed with the amine HN(R.

2

)R

13 after being converted to a carboxylic acid in the useful manner, whereby the ester is converted to 25 an a-amino group protected substituted phenylalanine amide. If R 3 is a substituted alkyl group, the a-amino group protected substituted phenylalanine ester is reduced to an aldehyde or an alcohol which, in turn, are converted to a - 30 halogen-substituted alkyl group, a hydroxyalkyl group, an aminoalkyl group, a methyl group, and so forth. Almost all types of Na-substituted amino acids are commercially available and readily purchasable; those which 5 are not commercially available can be produced by well-known established methods such as the one of reacting a-bromo carboxylic acid units with a primary amine (J. Med. Chem., 37, 2678 (1994)) and the one of treating an amino group protected amino acid or an ester thereof with a base and an 10 alkylating agent to effect its N-alkylation. The Na-amino group, as well as 1-Ala and y-Abu amino groups in amino acids can efficiently be protected with a fluorenyl methyloxycarbonyl (Fmoc) group, a tert butoxycarbonyl (Boc) group, a benzyloxycarbonyl (Z) group 15 and the like. A group that is preferably used to protect amino groups in solid-phase synthesis is an Fmoc group. Functional groups in side chains can be protected in various ways with various groups; the carboxyl group in the Asp, Glu or Aad residue is protected as a tert-butyl ester (OtBu); 20 the hydroxyl group in the Ser, Thr or Tyr residue is protected with a tert-butyl (tBu) group; the hydroxyl group in the Hse residue is protected with a triphenylmethyl (Trt) group; the imidazolyl group in the His residue, the side chain amino group in the Dab, Orn or Lys residue or the 25 indole group in the tryptophan residue is protected with a Boc group. Note that amino acid residues can be protected with other protective groups. Various methods may be used to activate the carboxyl -31group and they include: the use of benzotriazol-1-yl-oxy tris(dimethylamino)phosphonium hexafluorophosphate (BOP); the use of O-(7-azabenzotriazol-1-yl)-1,1,3, 3 tetramethyluronium hexafluorophosphate (HATU); the use of 5 diisopropyl carbodiimide (DIC); N-ethyl-N'-3 dimethylaminopropyl carbodiimide (WSCI); the use of dicyclohexyl carbodiimide (DCC); the use of diphenylphosphorylazide (DPPA); the combination of one of these reagents with 1-hydroxybenzotriazole (HOBT) or N 10 hydroxysuccinimide (HONSu); the mixed acid anhydride method using isobutyl chloroformate etc.; the use of an amino acid in which the a-carboxyl group is in the form of a pentafluorophenyl ester (OPfp), an amino acid in which the a-carboxyl group is in the form of a p-nitrophenyl ester 15 (ONP), or an amino acid in which the a-carboxyl group is in the form of an N-hydroxysuccinimide ester (OSu); the combination of one of these amino acids with HOBT. If necessary, a base such as triethylamine (TEA), diisopropylethylamine (DIEA), N-methylmorpholine (NMM) or 4 20 dimethylaminopyridine (DMAP) may be added to accelerate the reaction. A compound in which R 1 is N(R,)R 1 0 -CO- (where R 9 and R 10 have the same meanings as defined above) can be produced via various processes including the mixing, under stirring, of 25 an amino acid (A) with a reagent such as N,N' carbonyldiimidazole, phosgene, triphosgene or p-nitrophenyl chlorocarbonate, followed by addition of HN(R,)Rj 0 , as well R as the reacting of dipeptide units with R,(R 1 )N=C=O or -32

LU

R,(R3L )NC(=0)Cl. A compound in which R, is R 11 O-CO- can be produced via various processes including the coupling of a substituted phenylalanine amide with N-(C0 2

R

11 )-amino acid and the 5 reacting of the amino group in an amino acid (A) moiety with ClC0 2

R

1 1 To produce a compound in which R, is an alkyl group, an alkenyl group or an alkynyl group, a corresponding alkyl halide or aldehyde having the substituent protected as 10 required is used to alkylate the amino group in an amino acid (A) moiety in the usual manner, optionally followed by deprotection. The compounds of the invention can also be produced by applying the specific methods of production to be described 15 in the examples that follow. The subject application claims priority on the basis of Japanese Patent Application Nos. 255879/1997 and 186802/1998 and all disclosures in their specifications shall be incorporated herein by reference. 20 Examples On the pages that follow, the production of the compounds of the invention is described more specifically by reference to examples, to which the invention is by no means limited. In the following examples, unless otherwise noted, 25 the amino acid residues and Na-amino acid residues are in the L-form. In order to demonstrate the utility of the compounds of the invention, representative examples of them were -33 subjected to pharmacological tests on the motilin receptor antagonistic action and the results are described under Tests. The chemical structural formulae or chemical names of the compounds produced in the examples are set forth in 5 Tables A-1 to A-7 and Tables B-1 to B-11. - 34 - Table A-1 Example No. Structural formula or chemical name 1 Phe-Hyp-Tyr(3-tBu)-NH 2 2 Phe-Tic-Tyr(3-tBu)-NH 2 3 Phe-Thz-Tyr(3-tBu)-NH 2 4 Phe-2-Abz-Tyr(3-tBu)-NH 2 5 Phe-Phg-Tyr(3-tBu)-NH 2 6 Phe-D-Hyp-Tyr(3-tBu)-NH 2 7 Phe-Pro-Tyr(3-tBu)-NH 2 8 Phe-D-Pro-Tyr(3-tBu)-NH 2 9 Phe-Phg-Phe(3-tBu-4-methoxy)-NH2 10 Phe-Phe-Tyr(3-tBu)-NH 2 11 Phe-Val-Tyr(3-tBu)-NH 2 12 Phe-Phg-Tyr-NH 2 13 Phe-Ala-Tyr(3-tBu)-NH 2 14 Phe-Leu-Tyr( 3-tBu) -NH 2 15 Val-Phg-Tyr(3-tBu)-NH 2 16 Leu-Phg-Tyr(3-tBu)-NH 2 17 Phe-Gly-Tyr(3-tBu)-NH 2

RA-

1 -35 - Table A-2 Example No. Structural formula or chemical name 18A Phe-N-Me-Phg-Tyr(3-tBu)-NH 2 18B Phe-N-Me-D-Phg-Tyr(3-tBu)-NH 2 19 N-benzyl-N-(4-pyridylthioacetyl)-Phg Tyr(3-tBu)-NH 2 20 Phe-Phg-tYR(3-tBu)-OH 21 Phe-Tyr-Tyr(3-tBu)-NH 2 22 Phe-Hph-Tyr(3-tBu)-NH 2 23 Phe-Thi-Tyr(3-tBu)-NH 2 24 Phe-$-Ala-Tyr(3-tBu)-NH 2 25 Phe-y-Abu-Tyr(3-tBu) -NH 2 26 Phe-Aib-Tyr(3-tBu)-NH 2 27 Phe-Ile-Tyr(3-tBu)-NH 2 28 Phe-Chg-Tyr(3-tBu)-NH 2 29 Phe-Cha-Tyr(3-tBu)-NH 2 30 Phe-Tle-Tyr(3-tBu)-NH 2 31 Phe-Asp-Tyr(3-tBu)-NH 2 32 Phe-Glu-Tyr(3-tBu)-NH 2 33 Phe-Aad-Tyr(3-tBu)-NH 2 - 36 - Table A-3 Example No. Structural formula or chemical name 34 Phe-Asn-Tyr(3-tBu)-NH 2 35 Phe-Gln-Tyr(3-tBu)-NH 2 36 Phe-Cit-Tyr(3-tBu)-NH 2 37 Phe-Dab-Tyr(3-tBu)-NH 2 38 Phe-Qrn-Tyr(3-tBu)-NH 2 39 Phe-Lys-Tyr(3-tBu)-NH 2 40 Phe-Ser-Tyr(3-tBu)-NH 2 41 Phe-Hse-Tyr(3-tBu)-NH 2 42 Phe-Thr-Tyr(3-tBu)-NH 2 43 Phe-Abu-Tyr(3-tBu) -NH 2 44 Phe-Nva-Tyr(3-tBu) -NH 2 45 Phe-Met-Tyr(3-tBu)-NH 2 46 Phe-His-Tyr(3-tBu)-NH 2 47 Phe-Trp-Tyr(3-tBu)-NH 2 48 Phe-Tiq-Tyr(3-tBu) -NH 2 49 N-(4-pyridylthioacetyl)-PhgTyr(3tBu)-NH2 50 N- (1-benzocyclobutalecarboflyl) -Phg-Tyr( 3 tBu) -NH 2 -9 -37 )*C Table A-4 Example No. Structural formula or chemical name 51 N-(2-indolecarbonyl)-Phg-Tyr(3-tBu)-NH2 52 Tyr-Phg-Tyr(3-tBu)-NH 2 53 Phg-Phg-Tyr(3-tBu)-NH 2 54 Thi-Phg-Tyr(3-tBu)-NH 2 55 Trp-Phg-Tyr(3-tBu)-NH 2 56 His-Phg-Tyr(3-tBu)-NH 2 57 N- ((±)-3-phenylbutyryl)-Phg-Tyr(3-tBu)-NH2 58 N-(2-biphenylcarbonyl)-Phg-Tyr(3-tBu)-NH2 59 @-Ala-Phg-Tyr(3-tBu)-NH 2 60 Aib-Phg-Tyr(3-tBu)-NH 2 61 Ile-Phg-Tyr(3-tBu)-NH 2 62 Chg-Phg-Tyr(3-tBu)-NH 2 63 Cha-Phg-Tyr(3-tBu)-NH 2 64 Tle-Phg-Tyr(3-tBu)-NH 2 65 Asp-Phg-Tyr(3-tBu)-NH 2 66 Aad-Phg-Tyr(3-tBu)-NH 2 67 Asn-Phg-Tyr(3-tBu)-NH 2 -38 - Table A-5 Example No. Structural formula or chemical name 68 Gln-Phg-Tyr(3-tBu)

-NH

2 69 Cit-Phg-Tyr(3-tBu)-NH 2 70 Dab-Phg-Tyr(3-tBu)-NH 2 71 Lys-Phg-Tyr(3-tBu)-NH 2 72 Ser-Phg-Tyr(3-tBu)-NH 2 73 Hse-Phg-Tyr(3-tBu)-NH 2 74 Thr-Phg-Tyr(3-tBu)-NH 2 75 Abu-Phg-Tyr(3-tBu)-NH 2 76 Nva-Phg-Tyr(3-tBu)-NH 2 77 Met-Phg-Tyr(3-tBu)-NH 2 78 Pro-Phg-Tyr(3-tBu)-NH 2 79 Hyp-Phg-Tyr(3-tBu)-NH 2 80 Tic-Phg-Tyr(3-tBu)-NH 2 81 Tiq-Phg-Tyr(3-tBu)-NH 2 82 2-Abz-Phg-Tyr(3-tBu)-NH 2 83 Hph-Phg-Tyr( 3-tBu) -NH 2 84 N-(a-methylhydrocinnamoyl)-Phg-Tyr(3 tBu)-NH 2 RA-3 I -39 * C Table A-6 Example No. Structural formula or chemical name 85 N- (a-methylcinnamoyl) -Phg-Tyr(3-tBu) -NH 2 86 N-(3-quinolinecarbonyl)-Phg-Tyr(3-tBu)-NH 2 87 N-(3-furanacryloyl)-Phg-Tyr(3-tBu)-NH 2 88 Phe-D-Phg-Tyr(3-tBu)-NH 2 89 Phe-N-Me-Val-Tyr(3-tBu)-NH 2 90 N-(a-methylhydrocinnamoyl)-N-Me-D-Phg-Tyr(3 tBu)

-NH

2 91 Phe-Val-N-Me-Tyr(3-tBu)-NH 2 92 Phe-Phg-Tyr(3-tBu)-NHMe 93 Phe-Apc-Tyr(3-tBu)-NHMe 94 Phe-Ahc-Tyr(3-tBu)-NHMe 95 N-acetyl-transHyp(O-benzyl)-Tyr(3-tBu)-NHMe 96 Phe-Cha-Phe(3-tBu)-NH 2 97 N-(benzylaminocarbonyl)-N-Me-D-Phg-Tyr(3 tBu)-NH 2 98 N-(benzyloxycarbonyl)-Phg-Tyr(3-tBu)-NHMe 99 N- (benzyloxycarbonyl) -N-Me-Val-Tyr(3-tBu) -NH 2 100 N-((R)-3-phenylbutyryl)-Phg-Tyr(3-tBu)-NH2 101 N-((S)-3-phenylbutyryl)-Phg-Tyr(3-tBu)-NH2 102 N-((R)-3-phenylbutyryl)-D-Phg-Tyr(3-tBu)-NH2 40 - Table A-7 Example No. Structural formula or chemical name 103 N-((S)-3-phenylbutyryl)-D-Phg-Tyr(3-tBu)-NH 2 104 L-a-(3-methyl-2-butenyl)glycinoyl-N-Me-Val-Tyr (3-tBu)-NH 2 105 a-(4-pentynyl)glycinoyl-N-Me-Val-Tyr(3-tBu)-NH 2 106 a-(2-butynyl)glycinoyl-N-Me-Val-Tyr(3-tBu)-NH 2 107 N-((S)-3-phenylbutyryl)-N-Me-Val-Tyr(3-tBu)-NH 2 108 N-( (R)-3-phenylbutyryl)-N-Me-val-Tyr(3-tBu)-NH 2 109 N-($-aminohydrocinnamoyl)-N-Me-Val-Tyr(3-tBu)-NH 2 110 N-(2-amino-3-phenylpropyl)-Phg-Tyr(3-tBu)-NH 2 111 N-(2-amino-3-phenylpropyl)-N-Me-Phg-Tyr(3-tBu)

NH

2 112 N-(phenylpyruvinoyl) -N-Me-Val-Tyr(3-tBu) -NH 2 113 N-phenyl-Gly-N-Me-Val-Tyr(3-tBu)-NH 2 114 N-Me-N-phenyl-Gly-N-Me-Val-Tyr(3-tBu)-NH 2 115 N-(3-phenylbutyl)-Val-Tyr(3-tBu)-NH 2 116 N-(2-amino-3-phenylpropyl)-Val-Tyr(3-tBu)-NH 2 2-[(2-amino-3-phenylpropyl)amino]-N-[2-amino-1 117 [(3-tert-butyl-4-hydroxyphenyl)methyl)ethyl]-3 methylbutanamide N-[2-(3-tert-butyl-4-hydroxyphenyl)-1 118 methylethyll-3-methyl-2-(N-methyl-N phenylalaninoylamino ) but anamide 119 Phe-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 N-[2-(3-tert-butyl-4-hydroxyphenyl)-1 120 methylethyl]-3-methyl-2-(N-methyl-N-Me phenylalaninoylamino ) but anamide N-[2-(3-tert-butyl-4-hydroxyphenyl)-1 121 methylethyl]-N-Me-3-methyl-2-(N-methyl-N phenylalaninoylamino ) butanamide - 41 - Table B-1 OH t-Bu

H

2 N A-N NH 2 O H 0 O Ex. No. A Ex. No. A Ex. No. A 1 0 8 18B Me0 HO0 N N 2 10 H 0 21 H N ____ _ __ ___ HO' 3 1122 H 0 H N A, N (CH 2 ) 2 S H 3 C CH 3 4 -NH 13 H 0 23 H 0 5H 3 5 H 14 H 0 24 NNjtN H H N~ H3CN

CH

3 6 17 25 N

H

0 H 0 N -(CH2)3 Hd 0 Me O 0 7 N 18A M 26 H

H

3 C CH 3 -42- Table B-2 OH t-Bu

H

2 N A-N NH 2 H O Ex. No. A Ex. No. A Ex. No. A 27 034 27H 034 H 041H 0 rCH 3

CH

3

NH

2 OH 28 H 35 42 H

(CH

2

)

2 HO CH 3 O NH 2 29 H 0 36 43

(C

2

)

3 N HN

H

3 OC O NH 2 30 37H 0 44 H 0 H3COCH3 K K 3 NH 2

CH

3 31 0 38 045 H

HO

2 C

(CH

2 K

H

2 N

H

3 Cs 32 H 39 46 0

(CH

2

)

2

(CH

2

)

4 HO2C H 2 N \L NH 33 40 H 47 H (CH2 3 HO

HO

2 C N H A4 * -43- Table B-3 elR4

H

2 N rA-N

NH

2 O H 0 Ex. No. A

R

5 R4 9 H OCHs t-Bu 12 H 0 OH H N 48 N OH t-Bu 88 H 0 OH t-Bu N 89 Me 0 OH t-Bu

H

3 C-' CH 3 96 H 0 H t-Bu -44 - Tabl1e B-4 O 'OH R~A 0 t-Bu Rls N N NH 2 H 0 Ex. No. R'RA 90 CH3 ______ H 3 0 97 c CHa 'N N 102 . C3 H 103 CC3 H -~ -45- Table B-5 OH H O t-Bu N N NH 2 H 0 Ex. No. Ri Ex. No. R1 Ex. No. Ri 15 H 3 3 54 61 OH 3 16 H3H2 5562 H2

H

2 N )5663

H

2 N

H

2 N O 0 16 55 N 62

H

3 0 / 0 2 H 2 N

YH

2 N 0 49 N N 6 H

H

2 N

H

2 N O 0 0 50 57 O4H 3 Ol 1 H 3 64 H 3 O OH 3 O H

H

2 N O 51 58 65 H 2 N H 2 NJl H 0 'N0 52 HO 566 H0 2 0 H2N aCP) 02 0_ 02-I 53 'N60 67

NH

2

K-H

3 0 OH 3 0

H

2 NX 2

H

2 N 0 2 N -46 - Table B-6 OH H 0 t-Bu R 9 " N NH 2 HO Ex. No. Ri Ex. No. Ri Ex. No. Ri 68 H 2 N 75 NH 2 82

H

2 N

H

2 N O H 69 0yNH 2 76 CH 3 83 HN

H

2

H

2 N (OH 2

)

2

H

2 NJ'N1 0 H 2 N-'N< 00 0 70 N H 77 84

H

2 N H O H 3 C 0 0

H

2 N 8

(OH

2 ) N 'N

H

2 N'TO

H

0

H

3 C O 0 72 HO7 86

H

2 Ny N 0 7 3 8 0 8 0 8 7 C ,

H

2 N YN 0 H 0 0_ 74 H 3 O O 81

H

2 N ' 0 N

H

0 -47- Table B-7 Table B-8 OH

H

0 t-Bu OH F N NH 2 Me 0 t-Bu H 0 F N NH 2 t~c~H H0R 0 H Ex. No. R1 Ex. No. Ri Ex. No. R1 100 109 N , CH 3 N NH 0 0 0 101 104 H 3 C CH 3 112 N

TCH

3

H

2 N 0 O 0 110 105 H 113 N N

H

2 N O

%H

2 N 0 0 106 H 3 C N' CH3 H2N y O O 1071 0_CH3 0 108

.NCH

3 0 -48 - Table B-9 Table B-10 OH 'N t-u RA t-Bu R1"CH N -)L N R 3

R

1 -A- N H 3 H 0 R2 Ex. No. R -A- Ex. No. R1" RA R2 R3 92 91 H H CHs CONH2 H 0 H2N Q 93 118 H CHs H CH2 HNO

H

2 N 95 120 CH3 OHS H CH3 0,

H

3 C 00 98 11 H CH CH CH2 H 0 rH2O N 00 RA01, IN - 9 !T3 Table B-11 Ex. No. Structural Formula 19 NOH 0 t-Bu O H 20 OH O OH H11teBu N~N OH 2 N H O 116N .t.N NH HOH H t-Bu N~N NH 2 H No 116 "OH H 0N2t-BU N "-R N NH 2

H

2 N H 117 OH H 0 "t-Bu

H

2 N N NH 2 50 11*O In the following examples, HPLC retention times (RT in minutes) were measured by either one of the following methods a - e. Method a: HPLC was performed with HITACHI L-6300 using 5 Waters gBONDASPHERE 5p C18 300 A (300 angstroms, 3.9 x 150 mm) as a column. The eluting solution A was 0.1% trifluoro acetic acid (TFA) in distilled water and the eluting solution B was 0.1% TFA in acetonitrile (MeCN). The linear gradient was created by 0 - 70% of solution B for 35 minutes 10 at a flow rate of 1 ml/min. The detection wavelength was 280 nm (UV). Method b: Same as method a, except that the linear gradient was created by 0 - 60% of solution B for 30 minutes at a flow rate of 1 ml/min. 15 Method c: Same as method a, except that the linear gradient was created by 20 - 60% of solution B for 40 minutes at a flow rate of 1 ml/min. Method d: Same as method a, except that Waters pBONDASPHERE 5 p C18 100 A (100 angstroms, 3.9 x 150 mm) was used as a 20 column. Method e: Same as method a, except that HPLC was performed with SHIMADZU LC-10AD. If necessary, the crude product was purified by HPLC which was performed with Waters 600E or Gilson 306 using 25 YMC-Pack ODS (120 angstroms, 250 x 20 mm I.D.) as a column. The eluting solution A was 0.1% TFA in distilled water and the eluting solution B was 0.1% TFA in MeCN. The linear gradient was created at a flow rate of 10 ml/min, and the -51 detection wavelength was 280 nm (UV). Mass spectra (MA) were taken by EI-MS using SHIMADZU GCMS-QP1000 or GCMS-QP5050A or by FAB-MS using JASCO 70 250SEQ. 5 NMR was measured by the following method f or g. Method f: Burucher DX-500 (500 MHz) was used as a measuring instrument. Method g: JEOL JNM-EX-270 (270 MHz) was used as a measuring instrument. 10 Various commercial resins can conveniently be used as a solid phase and they include Rink Amide Resin of NovaBiochem, Fmoc-2,4-dimethoxy-4'-(carboxymethyloxy) benzhydrylamine linked to Aminomethyl Resin of Bachem, and Wang Resin of Watanabe Kagaku K.K., which were used as 15 appropriate in the following examples. Coupling in solid-phase synthesis can conveniently be performed by the following first to fifth methods, which were used as appropriate in the following examples. Method 1: Using 1.5 - 2 equivalents of an acid component 20 (e.g. amino acid, Na-substituted amino acid or carboxylic acid), 3 equivalents of BOP and 3 equivalents of HOBT (relative to resin), 3 ml of N,N-dimethylformamide (DMF) for 0.1 mmol of resin, and 6 equivalents of NMM, shaking was done for 1.5 - 2 hours. 25 Method 2: Using 1.5 - 2 equivalents of an acid component and 3 equivalents of HATU (relative to resin), 3 ml of DMF for 0.1 mmol of resin, and 6 equivalents of NMM, shaking was done for 1.5 - 2 hours. - 52 - Method 3: Using 1.5 - 2 equivalents of an acid component and 3 equivalents of HOBT (relative to resin), 3 ml of DMF for 0.1 mmol of resin, and 3.2 equivalents of DIC, shaking was done for 2 hours. 5 Method 4: Using 5 equivalents of an acid component and 0.1 equivalent of DMAP (relative to resin), 3 ml of DMF for 0.1 mmol of resin, and 5 equivalents of DIC, shaking was done for 4 hours. Method 5: Using 2 equivalents of an active ester (e.g. Pfp 10 ester) of an acid component and 3 equivalents of HOBT (relative to resin), and 3 ml of DMF for 0.1 mmol of resin, shaking was done for 2 hours. For constructing Na-substituted amino acid residues, the sixth method described below is convenient and was used 15 in the following examples as appropriate. Method 6: Using 10 equivalents of a substituted or unsubstituted bromoacetic acid, 3 ml of DMF for 0.1 mmol of resin, and 13 equivalents of DIC, shaking was done for 30 minutes; after filtering, reacylation was done under the 20 same conditions and repeated washing was effected with DMF; 60 equivalents of an amine dissolved in dimethyl sulfoxide (DMSO) was added to the mixture, which was shaken for 2 hours. The following is a specific procedure of solid-phase 25 synthesis. The reaction vessel is charged with a solid phase resin, such as Rink Amide Resin, which is swollen by addition of a suitable solvent such as DMF; subsequently, RAt 4 20% piperidine/DMF is added and repeated washing is effected - 53 with DMF. To the washed mixture, an acid component is coupled by method 1. Using either one of the first to sixth coupling methods, the procedure is repeated as many times as the acid components to be coupled. The order of steps of 5 deprotecting and cleaving the resin product is not fixed and they may be interchanged or performed simultaneously. The step of cleavage is completed by shaking in an aqueous solution of 95% TFA at room temperature for 30 - 45 minutes. After the end of the cleavage step, the resin is filtered 10 off and the filtrate is concentrated and dried under reduced pressure to give a phenylalanine derivative in crude form. The following is a specific method that may be employed to deprotect amino acids in solid-phase synthesis. If the resin is used in an amount of 0.025 - 0.1 mmol, an 15 Fmoc group can be removed by a process consisting of the steps of adding 5 ml of 20% piperidine/DMF for 0.1 mmol of the resin, shaking for 5 minutes, filtering, then adding another 5 ml of 20% piperidine/DMF, shaking for 20 - 30 minutes, filtering and repeated washing with DMF. If the 20 resin is used in an amount of 0.2 mmol, an Fmoc group can be removed by a process consisting of the steps of adding 7 ml of 20% piperidine/DMF, for 5 minutes, filtering, then adding another 7 ml of 20% piperidine/DMF, filtering and repeated washing with DMF. Boc, tBu and Trt groups can be removed in 25 the cleavage step, with deprotection and cleavage being effected simultaneously. Example 1 Phe-Hyp-Tyr(3-tBu)-NH 2 - 54 - (1) Synthesis of Tyr(3-tBu)-OMe To a solution of 25.0 g (0.108 mol) of Tyr-OMe*HCl in 500 ml of tert-butyl acetate, 18 ml (0.204 mol) of 70% HCl was added and the mixture was stirred at room temperature 5 for 4 days. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in 400 ml of ethyl acetate; thereafter, the solution was poured into 800 ml of a saturated aqueous solution of NaHCO 3 and the mixture was stirred. The organic layer was taken out 10 and washed first with a saturated aqueous solution of NaHCO,, then with saturated brine, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the resulting residue, 500 ml of ether was added and the mixture was stirred overnight at room 15 temperature. The precipitating crystals were recovered by filtration to give Tyr(3-tBu)-OMe in 10.9 g (40%). NMR(method gDMSO-d6):8 1.39(9H,s), 1.85(3H,brs), 2.81(lH,dd,J=14.0,7.6Hz), 3.02(1H,dd,J=14.0,5.lHz), 3.70(lH,dd,J=7.6,5.lHz), 3.73(3H,s), 6.57(1H,d,J=8.2Hz), 20 6.86(lH,dd,J=8.2,1.8Hz), 7.04(lH,d,J=1.8Hz) (2) Synthesis of Fmoc-Tyr(3-tBu)-OH To a solution of 2.0 g (8.0 mmol) of Tyr(3-tBu)-OMe in 40 ml of methanol, 8.8 ml (8.8 mmol) of 1 N aqueous sodium hydroxide was added dropwise under cooling with ice and the 25 mixture was stirred for 2 hours, followed by stirring at room temperature for additional 4 hours. The reaction mixture was concentrated under reduced pressure and 1 N HCl was added under cooling with ice for pH adjustment to 9; to 55 the reaction being maintained at pH 8 - 9, a solution of 3.0 g (8.8 mmol) of Fmoc-OSu in 1,4-dioxane (40 ml) and a saturated aqueous solution of sodium hydrogencarbonate were alternately added dropwise and the mixture was stirred at 5 room temperature for 1 day. After being rendered acidic with hydrochloric acid, the reaction mixture was extracted with ethyl acetate and the ethyl acetate layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was subjected 10 to silica gel column chromatography (eluting solvents were ethyl acetate:n-hexane = 1:1 and acetic acid supplemented ethyl acetate:n-hexane = 1:1); to remove the acetic acid used in eluting, the fractions were washed with water, dried with anhydrous magnesium sulfate and concentrated under 15 reduced pressure to give Fmoc-Tyr(3-tBu)-OH in 2.3 g (yield: 61%). NMR(method gCDCl 3 ): b 1.38(9H,s), 3.09(2H,m), 4.19(lH,m), 4.39(2H,d,J=7Hz), 4.64(lH,m), 5.19(lH,d,J=8Hz), 6.58(lH,d,J=8Hz), 6.84(lH,d,J=8Hz), 7.05(lH,br s), 20 7.26-7.77(8H,m) (3) Synthesis of Phe-Hyp-Tyr(3-tBu)-NH 2 A reaction vessel was charged with 22 mg (0.1 mmol) of Rink Amide Resin (0.45 mmol/g); after being swelled with DMF, the resin was treated with piperidine to remove Fmoc. 25 Subsequently, Fmoc-Tyr(3-tBu)-OH was coupled by method 1. After filtering and washing with DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, Fmoc-Hyp-OH was coupled by method 2. After filtering and washing with -56 * DMF, the resin was treated again with piperidine to remove Fmoc. Subsequently, Boc-Phe-OH was coupled by method 2. After the end of the reaction, filtering, washing with DMF and washing with methylene chloride (DCM) were performed and 5 cleavage was effected with 3 ml of a 95% aqueous solution of TFA. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 2 ml of DMF, followed by HPLC purification. The active fractions were collected, concentrated and freeze-dried to yield a TFA salt 10 of the titled compound in 23.2 mg. HPLC (method b):RT17.15 FAB-MS:497(M+H*) NMR(method fDMSO-d6): 8 1.32(9H,s), 1.75(1H,ddd,J=13,8,5Hz), 2.00(lH,dd, J=13,8Hz), 2.76(1H,dd,J=14,8Hz), 15 2.86(lH,dd,J=14,6Hz), 2.92(lH,dd,J=14,7Hz), 3.09(1H,dd,J=14,6Hz), 3.18(1H,dd,J=10,4Hz), 3.54(lH,d,J=1OHz), 4.25(lH,brs), 4.29-4.38(2H,m), 4.46(lH,dd,J=8,8Hz), 5.13(1H,d,J=3Hz), 6.65(lH,d,J=8Hz), 6.88(lH,dd,J=8,2Hz), 7.01(1H,d,J=2Hz), 7.02(lH,s),7.23 20 7.43(6H,m), 7.89(1H,d,J=8Hz), 8.09(3H,brs), 9.09(lH,s) Example 2 Phe-Tic-Tyr(3-tBu)-NH 2 Substituting Fmoc-Tic-OH for the Fmoc-Hyp-OH used in Example 1(3), the procedure of Example 1 was repeated to 25 yield a TFA salt of the titled compound in 34.4 mg. HPLC (method b):RT21.56 FAB-MS:543(M+H*) NMR(method gDMSO-d6): b 1.30(9H,s), 2.58-3.24(6H,m), - 57 - 4.27-4.85(5H,m), 6.56-7.41(14H,m), 7.81-8.36(4Hm), 9.09-9.11(lH,m) Example 3 Phe-Thz-Tyr(3-tBu)-NH 2 5 Substituting Fmoc-Thz-OH for the Fmoc-Hyp-OH used in Example 1(3), the procedure of Example 1 was repeated to yield a TFA salt of the titled compound in 20.2 mg. HPLC (method b):RT19.31 FAB-MS:499 (M+H*) 10 NMR(method gDMSO-d6): 8 1.32(9H,s), 2.70-3.15(6H,m), 4.16(lH,d,J=9Hz), 4.39(lH,m), 4.62(lH,m), 4.82(lH,t,J=7Hz), 5.02(lH,d,J=9Hz), 6.64(1H,d,J=8Hz), 6.82-7.41(9H,m), 8.00-8.13(4H,m), 9.10(1H,s) Example 4 15 Phe-2-Abz-Tyr(3-tBu)-NH 2 Substituting Fmoc-2-ABz-OH for the Fmoc-Hyp-OH used in Example 1(3), the procedure of Example 1 was repeated to yield a TFA salt of the titled compound in 6.9 mg. HPLC (method b):RT20.99 20 FAB-MS:503(M+H*) NMR(method gDMSO-d6): 8 1.29(9H,s), 2.81-3.10(4H,m), 4.28(lH,m),4.52(lH,m), 6.64(1H,d,J=8Hz), 6.94(lH,d,J=8Hz), 7.14-7.68(11H,m), 8.14(1H,d,J=8Hz), 8.31(2H,brs), 8.67(lH,d,J=8Hz), 9.10(1H,s), 11.27(1H,s) 25 Example 5 Phe-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Phg-OH for the Fmoc-Hyp-OH used in Example 1(3), the procedure of Example 1 was repeated RA-8 - 58 - (except that Fmoc-Phg-OH and Boc-Phe-OH were coupled by method 1) to yield a TFA salt of the titled compound in 17.7 mg. HPLC (method b):RT19.52 5 FAB-MS:517(M+H*) NMR(method fDMSO-d6): 8 1.32(9H,s), 2.74(lH,dd,J=14,8Hz), 2.89(lH,dd,J=14,5Hz), 2.92(lH,dd,J=14,8Hz), 3.07(lH,dd,J=14,5Hz), 4.17(lH,brs), 4.39(lH,ddd,J=8,8,5Hz), 5.60(1H,d,J=8Hz), 6.65(lH,d,J=8Hz), 6.87(lH,dd,J=8,1Hz), 10 6.98(1H,s), 7.06(lH,d,J=lHz), 7.10-7.50(11H,m), 8.09(3H,brs), 8.48(lH,d,J=8Hz), 9.06(1H,d,J=8Hz), 9.09(lH,s) Example 6 Phe-D-Hyp-Tyr(3-tBu)-NH 2 (1) Synthesis of Fmoc-D-Hyp-OH 15 262 mg (2.0 mmol) of D-Hyp-OH was dissolved in 5 ml of a saturated aqueous solution of sodium hydrogencarbonate under stirring and a mixture of 742 mg (2.2 mmol) of Fmoc OSu and 10 ml of 1,4-dioxane was added dropwise under cooling with ice; thereafter, and the mixture was stirred at 20 room temperature for 3 days. In the meantime, a saturated aqueous solution of sodium hydrogencarbonate was added as appropriate to keep the pH of the reaction mixture at 8 - 9. After being rendered acidic with hydrochloric acid under cooling with ice, the reaction mixture was subjected to 25 extraction with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel 59

-

column chromatography (eluting solvents were chloroform and acetic acid supplemented chloroform:methanol = 10:1); to remove the acetic acid used in eluting, the fractions were once concentrated under reduced pressure and dissolved again 5 in ethyl acetate; thereafter, the solution was washed with water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give a colorless powder in 660 mg (93%). NMR(method gDMSO-d6): 8 1.89-2.29(2H,m), 3.26-3.56(3H,m), 10 4.10-4.47(4H,m), 5.15(lH,br s), 7.28-7.94(8H,m), 12.64(lH,brs) (2) Synthesis of Phe-D-Hyp-Tyr(3-tBu)-NH 2 A reaction vessel was charged with 213 mg (0.1 mmol) of Rink Amide Resin (0.47 mmol/g); after being swelled with 15 DMF, the resin was treated with pyridine to remove Fmoc. Subsequently, Fmoc-Tyr(3-tBu)-OH was coupled by method 1. After filtering and washing with DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, Fmoc-D-Hyp-OH was coupled by method 2. After filtering and washing with 20 DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, Fmoc-Phe-OH was coupled by method 2. After filtering and washing with DMF, the resin was treated again with piperidine to remove Fmoc. After the end of the reaction, filtering, washing with DMF and washing with DCM 25 were performed and cleavage was effected with 3 ml of a 95% aqueous solution of TFA. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 2 ml of DMF, followed by HPLC purification. -60 - The active fractions were collected, concentrated and freeze-dried to yield a TFA salt of the titled compound in 21.5 mg. HPLC (method d):RT16.68 FAB-MS:497(M+H*) 5 NMR(method gDMSO-d6):b 1.32(9H,s), 1.45-1.76(2H,m), 2.62-3.09(4H,m), 3.59-4.78(6H,m), 5.14(lH,br s), 6.64(lH,d,J=8Hz), 6.82(lH,d,J=6Hz), 7.00(lH,s), 7.13(2H,s), 7.23-7.36(5H,m), 8.16(3H,brs), 8.41(lH,d,J=9Hz), 9.08(lH, s) Example 7 10 Phe-Pro-Tyr(3-tBu)-NH 2 Substituting Fmoc-Pro-OH-AcOEt for the Fmoc-d-Hyp-OH used in Example 6(2), the procedure of Example 6(2) was repeated to yield a TFA salt of the titled compound in 27.0 mg. 15 HPLC (method b):RT18.87 FAB-MS:481(M+H*) NMR(method gDMSO-d6): 8 1.32(9H,s), 1.38-2.10(4H,m), 2.75(lH,dd,J=14,9Hz), 2.84-3.85(5H,m), 4.25-4.49(3H,m), 6.64(lH,d,J=8Hz), 6.82-7.35(9H,m), 7.70-8.30(4H,m), 20 9.09(1H,s) Example 8 Phe-D-Pro-Tyr(3-tBu)-NH 2 Substituting Fmoc-D-Pro-OH-AcOEt for the Fmoc-D-Hyp-OH used in Example 6(2), the procedure of Example 6(2) was 25 repeated to yield a TFA salt of the titled compound in 33.6 mg. HPLC (method b):RT19.87 FAB-MS:481(M+H*) - 61 - NMR(method gDMSO-d6): 8 1.31(9H,s), 1.41-2.04(4H,m), 2.55-3.51(6H,m), 4.15-4.70(3H,m), 6.61-6.67(lH,m), 6.80-6.83(lH,m), 6.98-7.01(lH,m), 7.12-7.34(7H,m), 8.02-8.39(4H,m), 9.08(lH,s) 5 Example 9 Phe-Phg-Phe(3-tBu-4-methoxy)-NH 2 (1) Synthesis of Z-Tyr(3-t-Bu)-OMe To a solution of Tyr(3-tBu)-OMe (1.1 g) in H 2 0 (10 ml), 0.7 g (6.57 mmol) of NaHCO 3 and 0.92 ml (6.57 mmol) of Z-Cl 10 were added under cooling with ice and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced 15 pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n hexane = 1:2) to give Z-Tyr(3-t-Bu)-OMe in 1.44 g (85%). NMR(method gCDCl 3 ): 8 1.36(9H,s), 3.04(2H,brd,J=5.6Hz), 3.72(3H,s), 4.57-4.68(lH,m), 4.97(lH,brs), 5.10(2H,s), 20 5.20(lH,brd,J=7.9Hz), 6.55(lH,d,J=7.9Hz), 6.78(1H,dd,J=2.0,7.9Hz), 6.95(lH,d,J=2.OHz), 7.26-7.41(5H,m) (2) Synthesis of Z-Phe(3-tBu-4-methoxy)-OMe To a solution of Z-Tyr(3-tBu)-OMe (0.4 g) in acetone (3 ml), 0.22 g (1.56 mmol) of K 2 C0 3 and 0.65 ml (10.4 mmol) 25 of methyl iodide were added at room temperature and the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was subjected to silica gel column -62 chromatography (eluting solvent; ethyl acetate:n-hexane = 1:2) to give Z-Phe(3-tBu-4-methoxy)-OMe in 0.10 g (24%). NMR(method gCDCl 3 ):5 1.33(9H,s), 3.05(2H,brd,J=5.6Hz), 3.72(3H,s), 3.81(3H,s), 4.57-4.68(lH,m), 5.10(2H,s), 5 5.19(1H,brd,J=7.9Hz), 6.76(1H,d,J=8.2Hz), 6.90(1H,dd,J=2.0,8.2Hz), 6.96(1H,d,J=2.OHz), 7.26-7.40(5H,m) (3) Synthesis of Phe(3-tBu-4-methoxy)-OMe To a solution of Z-Phe(3-tBu-4-methoxy)-OMe (0.17 g) in methanol (2 ml), 10% palladium carbon (0.02 g) was added 10 at room temperature and the mixture was stirred in a hydrogen atmosphere for 20 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent was ethyl acetate) to 15 give Phe(3-tBu-4-methoxy)-OMe in 88 mg (77%). EI-MS: 265(M*) NMR(method gCDCl 3 ): 8 1.35(9H,s), 2.81(1H,dd,J=13.6,7.8Hz), 3.02(1H,dd,J=13.6,5.OHz), 3.67-3.71(lH,m), 3.73(3H,s), 3.81(3H,s), 6.80(1H,d,J=8.2Hz), 7.00(1H,dd,J=2.0,8.2Hz), 20 7.05(lH,d,J=2.OHz) (4) Synthesis of Fmoc-Phe(3-tBu-4-methoxy)-OH To a solution of 87 mg (0.33 mmol) of Phe(3-tBu-4 methoxy)-OMe in 2 ml of methanol, 0.4 ml (0.4 mmol) of 1 N aqueous sodium hydroxide was added dropwise under cooling 25 with ice and the mixture was stirred for 1 hour, followed by stirring for additional 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and adjusted to pH 9 by addition of 1 N hydrochloric acid and a -63 saturated aqueous solution of sodium hydrogencarbonate. To the thus adjusted reaction mixture, a solution of 122 mg (0.36 mmol) of Fmoc-OSu in 2 ml of 1,4-dioxane was added dropwise and the mixture was stirred for 3 hours at room 5 temperature. The reaction mixture was rendered acidic with hydrochloric acid and extracted with ethyl acetate; the ethyl acetate layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by preparative thin 10 layer chromatography (developing solvents were CHC1 3 and CHCl 3 :methanol = 4:1) to give Fmoc-Phe(3-tBu-4-methoxy)-OH in 125 mg (80%). NMR(method gCDCl 3 ): 8 1.33(9H,s), 2.99-3.21(2H,m), 3.76(3H,s), 4.12(lH,m), 4.32(2H,m), 4.57(lH,br s), 15 5.25(lH,d,J=6Hz), 6.74(1H,dJ=8Hz), 6.95(lH,d,J=8Hz), 7.06(lH,br s), 7.22-7.74(8H,m) (5) Synthesis of Phe-Phg-Phe(3-tBu-4-methoxy)-NH 2 Substituting Fmoc-Phe(3-tBu-4-methoxy)-OH for the Fmoc-Tyr(3-tBu)-OH used in Example 5 and using 213 mg (0.1 20 mmol) of Rink Amide Resin (0.47 mmol/g) as a resin, the procedure of Example 5 was repeated to yield a TFA salt of the titled compound in 18.8 mg. HPLC (method e):RT22.70 FAB-MS:531(M+H*) 25 NMR(method fDMSO-d6): 8 1.30(9H,s), 2.78(lH,dd,J=14,9Hz), 2.90(lH,dd,J=14,8Hz), 2.94(lH,dd,J=14,5Hz), 3.04(lH,dd,J=14,5Hz), 3.69(3H,s), 4.17(lH,brs), 4.43(lH,ddd,J=14,9,8Hz), 5.60(lH,d,J=8Hz), 6.82(lH,d,J=8Hz), - 64 - 7.01(1H,s), 7.06(lH,dd,J=8,lHz), 7.15(lH,d,J=lHz), 7.17-7.48(11H,m), 8.08(3H,brs), 8.54(lH,d,J=8Hz), 9.06(lH,d,J=8Hz) Example 10 5 Phe-Phe-Tyr(3-tBu)-NH 2 Substituting Fmoc-Phe-OH for the Fmoc-Phg-OH used in Example 5 and using 213 mg (0.1 mmol) of Rink Amide Resin (0.47 mmol/g) as a resin, the procedure of Example 5 was repeated to yield a TFA salt of the titled compound in 10 20.5 g. HPLC (method e):RT19.41 FAB-MS:531(M+H*) NMR(method fDMSO-d6): 8 1.31(9H,s), 2.74(lH,dd,J=14,8Hz), 2.82(lH,dd,J=14,9Hz), 2.87(lH,dd,J=14,9Hz), 15 2.89(lH,dd,J=14,5Hz), 3.03(1H,dd,J=14,4Hz), 3.10(lH,dd,J=14,4Hz), 4.00(lH,brs), 4.40(lH,ddd,J=8,8,5Hz), 4.61(lH,ddd,J=9,8,4Hz), 6.65(1H,d,J=8Hz), 6.87(lH,dd,J=8,2Hz), 7.00-7.10(2H,m), 7.15-7.28(1OH,m), 7.30(lH,s), 7.98(3H,brs), 8.23(lH,d,J=8Hz), 8.66(lH,d,J=8Hz), 20 9.07(1H,s) Example 11 Phe-Val-Tyr(3-tBu)-NH 2 Substituting Fmoc-Val-OH for the Fmoc-Phg-OH used in Example 5 and using 213 mg (0.1 mmol) of Rink Amide 25 Resin (0.47 mmol/g) as a resin, the procedure of Example 5 was repeated to yield a TFA salt of the titled compound in 28.4 mg. HPLC (method e):RT18.68 - 65 - FAB-MS:483(M+H*) NMR(method fDMSO-d6): 8 0.83(3H,d,J=7Hz), 0.84(3H,d,J=7Hz), 1.31(9H,s), 1.96(1H,dqq,J=7,6,6Hz), 2.71(1H,dd,J=14,9Hz), 2.86(lH,dd,J=14,6Hz), 2.88(lH,dd,J=14,8Hz), 5 3.03(lH,dd,J=14,5Hz), 4.13(lH,brs), 4.25(1H,dd,J=9,6Hz), 4.40(lH,ddd,J=9,8,6Hz), 6.65(1H,d,J=8Hz), 6.88(lH,dd,J=8,2Hz), 6.99(lH,s), 7.05(lH,d,J=2Hz), 7.13 7.25(5H,m), 7.35(1H,s), 8.05(1H,d,J=8Hz), 8.07(3H,brs), 8.43(1H,d,J=9Hz), 9.08(lH,s) 10 Example 12 Phe-Phg-Tyr-NH 2 Substituting Fmoc-Tyr(tBu)-OH for the Fmoc-Tyr(3-tBu) OH used in Example 5 and using 213 mg (0.1 mmol) of Rink Amide Resin (0.47 mmol) as a resin, the procedure of Example 15 5 was repeated to yield a TFA salt of the titled compound in 21.7 mg. HPLC (method e):RT13.40 FAB-MS:461(M+H*) NMR(method fDMSO-d6): b 2.73(lH,dd,J=14,8Hz), 20 2.89(lH,dd,J=14,5Hz), 2.93(lH,dd,J=14,8Hz), 3.07(lH,dd,J=14,5Hz), 4.17(lH,dd,J=8,5Hz), 4.39(lH,ddd,J=8,8,5Hz), 5.59(1H,d,J=8Hz), 6.63(2H,d), 6.99(1H,s), 7.03(2H,d), 7.20-7.50(11H,m), 8.05(3H,brs), 8.45(lH,d,J=8Hz), 9.06(1H,d,J=8Hz), 9.16(1H,s) 25 Example 13 Phe-Ala-Tyr(3-tBu)-NH 2 Substituting Fmoc-Ala-OH-H 2 0 for the Fmoc-D-Hyp-OH used in Example 6(2), the procedure of Example 6(2) was - 66 repeated (except that Fmoc-Ala-OH'H 2 0 and Fmoc-Phe-OH were coupled by method 1) to yield a TFA salt of the titled compound in 27.8 mg. HPLC (method e):RT17.82 5 FAB-MS:455(M+H*) NMR(method fDMSO-d6): 8 1.22(3H,d,J=6Hz), 1.31(9H,s), 2.71(lH,dd,J=14,9Hz), 2.86(lH,dd,J=14,9Hz), 2.87(lH,dd,J=14,5Hz), 3.06(lH,dd,J=14,5Hz), 4.04(lH,brs), 4.30-4.40(2H,m), 6.65(1H,d,J=8Hz), 6.86(1H,dd,J=8,2Hz), 10 7.03(lH,d,J=2Hz), 7.04(1H,s), 7.17-7.27(5H,m), 7.39(lH,s), 8.01(lH,d,J=8Hz), 8.06(3H,brs), 8.58(lH,d,J=8Hz), 9.08(1H,s) Example 14 Phe-Leu-Tyr(3-tBu)-NH 2 Substituting Fmoc-Leu-OH for the Fmoc-Ala-OH-H 2 0 used 15 in Example 13, the procedure of Example 13 was repeated to yield a TFA salt of the titled compound in 31.6 mg. HPLC (method e):RT20.02 FAB-MS:497(M+H*) NMR(method fDMSO-d6): 8 0.86(3H,d,J=6Hz), 0.89(3H,d,J=6Hz), 20 1.31(9H,s), 1.43(2H,dd,J=7,7Hz), 1.61(lH,tqq,J=7,6,6Hz), 2.73(lH,dd,J=14,8Hz), 2.81-2.93(2H,m), 3.09(1H,dd,J=14,5Hz), 4.04(lH,brs), 4.31-4.42(2H,m), 6.64(1H,d,J=8Hz), 6.85(1H,dd,J=8,2Hz), 7.02(1H,d,J=2Hz), 7.03(lH,s), 7.18 7.26(5H,m), 7.37(lH,s), 8.00(1H,d,J=8Hz), 8.05(3H,brs), 25 8.56(lH,d,J=8Hz), 9.08(lH,s) Example 15 Val-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Val-OH for the Fmoc-Phe-OH used in RA - 67 - Example 6(2) and also substituting Fmoc-Phg-OH for Fmoc-D Hyp, the procedure of Example 6(2) was repeated (except that Fmoc-Val-OH and Fmoc-Phg-OH were coupled by method 1) to yield a TFA salt of the titled compound in 18.2 mg. 5 HPLC (method e):RT17.64 FAB-MS:469(M+H*) NMR(method gDMSO-d6): 8 0.90(3H,d,J=7Hz), 0.91(3H,d,J=7Hz), 1.31(9H,s), 2.02(lH,m), 2.72(1H,dd,J=14,9Hz), 2.87(1H,dd,J=14,5Hz), 3.77(lH,m), 4.42(lH,m), 10 5.61(lH,d,J=8Hz), 6.60(lH,d,J=8Hz), 6.80(lH,dd,J=8,2Hz), 6.99-7.01(2H,m), 7.25-7.45(6H,m), 8.03(3H,br s), 8.46(lH,d,J=8Hz), 8.94(lH,d,J=8Hz), 9.07(lH,s) Example 16 Leu-Phg-Tyr(3-tBu)-NH 2 15 Substituting Fmoc-Leu-OH for the Fmoc-Phe-OH used in Example 6(2) and also substituting Fmoc-Phg-OH for Fmoc-D Hyp, the procedure of Example 6(2) was repeated (except that Fmoc-Leu-OH and Fmoc-Phg-OH were coupled by method 1) to yield a TFA salt of the titled compound in 19.3 mg. 20 HPLC (method e):RT18.74 FAB-MS:483(M+H*) NMR(method gDMSO-d6): 8 0.87(3H,d,J=7Hz), 0.89(3H,d,J=7Hz), 1.32(9H,s), 1.50-1.65(3H,m), 2.73(1H,dd,J=14,8Hz), 2.87(lH,dd,J=14,5Hz), 3.93(lH,m), 4.41(lH,m), 25 5.59(1H,d,J=8Hz), 6.62(1H,d,J=8Hz), 6.81(lH,dd,J=8,lHz), 6.99-7.01(2H,m), 7.28-7.44(6H,m), 8.06(3H,br s), 8.43(1H,d,J=8Hz), 9.08(lH,s), 9.09(lH,d,J=8Hz) RA~ Example 17 -68 Phe-Gly-Tyr(3-tBu)-NH 2 Substituting Fmoc-Gly-OPfp for the Fmoc-Phg-OH used in Example 5 and using 213 mg (0.1 mmol) of Rink Amide Resin (0.47 mmol/g) as a resin, the procedure of Example 5 was 5 repeated (except that Fmoc-Gly-OPfp was coupled by method 5) to yield a TFA salt of the titled compound in 20.8 mg. HPLC (method d):RT17.23 FAB-MS:441(M+H*) NMR(method fDMSO-d6): 5 1.32(9H,s), 2.64(lH,dd,J=14,9Hz), 10 2.88(lH,dd,J=14,5Hz), 2.91(lH,dd,J=14,8Hz), 3.07(lH,dd,J=14,5Hz), 3.65(lH,dd,J=17,6Hz), 3.90(lH,dd,J=17,6Hz), 4.07(lH,brs), 4.36(lH,ddd,J=9,8,5Hz), 6.64(1H,d,J=8Hz), 6.85(lH,dd,J=8,lHz), 7.01(lH,d,J=lHz), 7.06(1H,s), 7.20-7.35(5H,m), 7.45(lH,s), 8.10(3H,brs), 15 8.19(lH,d,J=8Hz),8.62(lH,dd,J=6,6Hz), 9.09(1H,s) Example 18 18A: Phe-N-Me-Phg-Tyr(3-tBu)-NH 2 18B: Phe-N-Me-D-Phg-Tyr(3-tBu)-NH 2 A reaction vessel was charged with 213 mg (0.1 mmol) 20 of Rink Amide Resin (0.47 mmol/g); after being swelled with DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, Fmoc-Tyr(3-tBu)-OH was coupled by method 1. After filtering and washing with DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, using a 25 bromophenylacetic acid and 40% aqueous methylamine, coupling was done by method 6 to construct Na-substituted amino acid residues. After filtering and washing with DMF, Boc-Phe-OH A~ was coupled by method 2. After the end of the reaction, - 69 filtering and washing with DMF and DCM were effected, followed by cleavage with 3 ml of 95% aqueous TFA. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 2 ml of DMF, followed by HPLC 5 purification. The active fractions were collected, concentrated and freeze-dried to yield TFA salts of the titled compounds in respective amounts of 21.9 mg (18A) and 12.9 mg (18B). 18A HPLC (method c):RT16.64 10 FAB-MS:531(M+H*) NMR(method gDMSO-d6): 6 1.27(9H,s), 2.45(3H,s), 2.62-3.11(4H,m), 4.60(2H,m), 6.07(lH,s), 6.41(2H,d,J=7Hz), 6.56(1H,d,J=8Hz), 6.71(1H,d,J=8Hz), 7.05-7.32(11H,m), 8.29(3H,br s), 8.39(1H,dJ=9Hz), 9.13(lH,s) 15 18B HPLC (method c):RT14.20 FAB-MS:531(M+H*) NMR(method fDMSO-d6): 5 1.28(9H,s), 2.47(3H,s), 2.70(lH,dd,J=14,9Hz), 2.87(lH,dd,J=14,5Hz), 2.96(2H,d,J=7Hz), 4.42(1H,ddd,J=5,9,8Hz), 4.49(lH,brs), 6.27(1H,s), 20 6.62(1H,d,J=8Hz), 6.92(1H,dd,J=8,2Hz), 7.00(1H,s), 7.05 7.36(11H,m), 7.45(lH,s), 8.14(3H,brs), 8.32(1H,d,J=8Hz), 9.04(lH,s) Example 19 N-benzyl-N-(4-pyridylthioacetyl)-Phg-Tyr(3-tBu)-NH 2 25 A reaction vessel was charged with 213 mg (0.1 mmol) of Rink Amide Resin (0.47 mmol/g); after being swelled with DMF, the resin was treated with piperidine to remove Fmoc. RA Subsequently, Fmoc-Tyr(3-tBu)-OH was coupled by method 1. -70 4U After filtering and washing with DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, using a bromophenylacetic acid and benzylamine, coupling was done by method 6 to construct Na-substituted amino acid residues. 5 After filtering and washing with DMF, a mixture of 1.5 ml of DMF, 1.5 ml of NMM and 34 mg (0.2 mmol) of 4-pyridyl thioacetic acid, and 114 mg (0.3 mmol) of HATU were added, followed by shaking for 2 hours to effect coupling. After the end of the reaction, filtering, and washing with DMF, 10 DCM and methanol were effected and the resin was dried. Cleavage was performed with 3 ml of 95% aqueous TFA. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 2 ml of DMF, followed by HPLC purification. The active fractions were collected, 15 concentrated and freeze-dried to yield a TFA salt of the titled compound in 19.8 mg as a mixture of diastereomers. HPLC (method b):RT22.90,23.39 FAB-MS:611(M+H*) Example 20 20 Phe-Phg-Tyr(3-tBu)-OH Using 274 mg (0.2 mmol) of Wang Resin (0.73 mmol/g) as a resin, the procedure of Example 5 was repeated (except that Fmoc-Tyr(3-tBu)-OH was coupled by method 4) to yield a TFA salt of the titled compound in 31.2 mg. 25 HPLC (method b):RT20.62 FAB-MS:518(M+H*) NMR(method fDMSO-d6): 8 1.31(9H,s), 2.82(lH,dd,J=14,8Hz), 2.89(lH,dd,J=14,8Hz), 2.94(lH,dd,J=14,5Hz), - 71 -94 3.04(1H,dd,J=14,5Hz), 4.10(lH,brs), 4.35(1H,ddd,J=8,8,5Hz), 5.61(lH,d,J=8Hz), 6.66(lH,d,J=8Hz), 6.84(lH,dd,J=8,1Hz), 7.04(1H,d,J=lHz), 7.15-7.45(10H,m), ca7.9(ambiguous,br), 8.68(1H,d,J=8Hz), 9.02(1H,d,J=8Hz), 9.14(1H,s) 5 Example 21 Phe-Tyr-Tyr(3-tBu)-NH 2 Substituting Fmoc-Tyr(tBu)-OH for the Fmoc-Phg-OH used in Example 5 and using 107 mg (0.05 mmol) of Rink Amide Resin (0.47 mmol/g) as a resin, the procedure of Example 5 10 was repeated (except that after cleavage, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 3 ml of methanol, followed by another concentrating under reduced pressure) to yield a TFA salt of the titled compound in 15.8 mg. 15 HPLC (method e):RT18.78 FAB-MS:547(M+H*) Example 22 Phe-Hph-Tyr(3-tBu)-NH 2 Substituting Fmoc-Hph-OH for the Fmoc-Tyr(tBu)-OH used 20 in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 19.4 mg. HPLC (method e):RT21.53 FAB-MS:545(M+H*) Example 23 25 Phe-Thi-Tyr(3-tBu)-NH 2 Substituting Fmoc-Thi-OH for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 21.5 mg. -72- HPLC (method e):RT19.65 FAB-MS:537(M+H*) Example 24 Phe-P-Ala-Tyr(3-tBu)-NH 2 5 Substituting Fmoc-$-Ala-OH for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 29.4 mg. HPLC (method e):RT17.51 FAB-MS:455(M+H*) 10 Example 25 Phe-y-Abu-Tyr(3-tBu)-NH 2 Substituting Fmoc-y-Abu-OH for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 34.4 mg. 15 HPLC (method e):RT17.59 FAB-MS:469(M+H*) Example 26 Phe-Aib-Tyr(3-tBu)-NH 2 Substituting Fmoc-Aib-OH for the Fmoc-Tyr(tBu)-OH used 20 in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 27.2 mg. HPLC (method e):RT19.82 FAB-MS:469(M+H*) Example 27 25 Phe-Ile-Tyr(3-tBu)-NH 2 Substituting Fmoc-Ile-OPfp for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated (except that Fmoc-Ile-OPfp was coupled by method 5) to yield 73 - -*,*r)

LU

a TFA salt of the titled compound in 18.9 mg. HPLC (method e):RT19.35 FAB-MS:497(M+H*) Example 28 5 Phe-Chg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Chg-OH for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated. The crude product was dissolved in DMSO and purified by HPLC; the active fractions were collected, concentrated and 10 freeze-dried to yield a TFA salt of the titled compound in 10.1 mg. HPLC (method e):RT20.54 FAB-MS:523(M+H*) NMR(method g,DMSO-d6): 8 0.82-1.20(5H,m), 1.31(9H,s), 1.46-1. 15 73(6H,m), 2.70(lH,dd,J=14,9Hz), 2.82-2.90(2H,m), 3.02(lH,dd, J=14,5Hz), 4.10(lH,br s), 4.24(lH,t,J=8Hz), 4.42(lH,dd,J=13, 5Hz), 6.64(1H,d,J=8Hz), 6.86(lH,dd,J=8,lHz), 7.00(1H,s), 7.0 4(lH,d,J=lHz), 7.18(5H,s), 7.34(lH,s), 8.01-8.04(4H,m), 8.42 (lH,d,J=9Hz), 9.07(1H,s) 20 Example 29 Phe-Cha-Tyr(3-tBu)-NH 2 Substituting Fmoc-Cha-OH for the Fmoc-Chg-OH used in Example 28, the procedure of Example 28 was repeated to yield a TFA salt of the titled compound in 10.0 mg. 25 HPLC (method e):RT22.35 FAB-MS:537(M+H*) MMR(method gDMSO-d6): 8 0.81-1.25(5H,m), 1.31(9H,s), 1.40-1.77(8H,m), 2.68-2.89(3H,m), 3.09(1H,dd,J=14,4Hz), !9- 74 - 4.02(lH,br s), 4.33-4.38(2H,m), 6.63(1H,d,J=8Hz), 6.85(lH,dd,J=8,1Hz), 7.01-7.04(2H,m), 7.23(5H,s), 7.35(lH,s), 7.98(1H,d,J=8Hz), 8.03(3H,br s), 8.55(1H,d,J=8Hz), 9.07(1H,s) 5 Example 30 Phe-Tle-Tyr(3-tBu)-NH 2 Substituting Fmoc-Tle-OH for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 23.8 mg. 10 HPLC (method e):RT18.87 FAB-MS:497(M+H*) Example 31 Phe-Asp-Tyr(3-tBu)-NH 2 Substituting Fmoc-Asp(OtBu)-OH for the Fmoc-Tyr(tBu) 15 OH used in Example 21 and using MeCN instead of methanol to dissolve the residue, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 30.2 mg. HPLC (method e):RT17.13 20 FAB-MS:499(M+H*) Example 32 Phe-Glu-Tyr(3-tBu)-NH 2 Substituting Fmoc-Glu(OtBu)-OH for the Fmoc-Tyr(tBu) OH used in Example 21 and using MeCN instead of methanol as 25 a solvent to dissolve the residue, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 28.2 mg. HPLC (method e):RT17.37 - 75 LU FAB-MS:513(M+H*) Example 33 Phe-Aad-Tyr( 3-tBu) -NH 2 Substituting Fmoc-Aad(OtBu)-OH for the Fmoc-Tyr(tBu) 5 OH used in Example 21 and using MeCN instead of methanol as a solvent to dissolve the residue, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 31.8 mg. HPLC (method e):RT17.54 10 FAB-MS:527(M+H*) Example 34 Phe-Asn-Tyr(3-tBu)-NH 2 Substituting Fmoc-Asn-OH for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated to 15 yield a TFA salt of the titled compound in 21.5 mg. HPLC (method e):RT17.04 FAB-MS:498(M+H*) Example 35 Phe-Gln-Tyr(3-tBu)-NH 2 20 Substituting Fmoc-Gln-OPfp for the Fmoc-Tyr(tBu)-OH used in Example 21), the procedure of Example 21 was repeated (except that Fmoc-Gln-OPfp was coupled by method 5) to yield a TFA salt of the titled compound in 27.2 mg. HPLC (method e):RT16.90 25 FAB-MS:512(M+H*) Example 36 Phe-Cit-Tyr(3-tBu)-NH 2 SRA4, Substituting Fmoc-Cit-OH for the Fmoc-Tyr(tBu) -OH used -76in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 25.6 mg. HPLC (method e):RT16.68 FAB-MS:541(M+H*) 5 Example 37 Phe-Dab-Tyr(3-tBu)-NH 2 Substituting Fmoc-Dab(Boc)-OH for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 29.1 mg. 10 HPLC (method e):RT16.07 FAB-MS:484(M+H*) Example 38 Phe-Orn-Tyr(3-tBu)-NH 2 Substituting Fmoc-Orn(Boc)-OH for the Fmoc-Tyr(tBu)-OH 15 used in Example 21), the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 33.7 mg. HPLC (method e):RT16.04 FAB-MS:498(M+H*) 20 Example 39 Phe-Lys-Tyr(3-tBu)-NH 2 Substituting Fmoc-Lys(Boc)-OH for the Fmoc-Tyr(tBu)-OH used in Example 21), the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 25 29.2 mg. HPLC (method e):RT16.49 FAB-MS:512(M+H*) Example 40 RA-7 77

*W

Phe-Ser-Tyr(3-tBu)-NH 2 Substituting Fmoc-Ser(tBu)-OH for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 25.5 mg. 5 HPLC (method e):RT17.31 FAB-MS:471(M+H*) Example 41 Phe-Hse-Tyr(3-tBu)-NH 2 Substituting Fmoc-Hse(Trt)-OH for the Fmoc-Tyr(tBu)-OH 10 used in Example 21, the procedure of Example 21 was repeated. After concentrating the cleavage cocktail, re-precipitation was effected with diethyl ether to yield a TFA salt of the titled compound in 7.8 mg. HPLC (method e):RT17.64 15 FAB-MS:485(M+H*) Example 42 Phe-Thr-Tyr(3-tBu)-NH 2 Substituting Fmoc-Thr(tBu)-OH for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated 20 to yield a TFA salt of the titled compound in 24.1 mg. HPLC (method e):RT17.40 FAB-MS:485(M+H*) Example 43 Phe-Abu-Tyr(3-tBu)-NH 2 25 Substituting Fmoc-Abu-OH for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 19.6 mg. HPLC (method e):RT18.55 -78- FAB-MS:469(M+H*) Example 44 Phe-Nva-Tyr(3-tBu)-NH 2 Substituting Fmoc-Nva-OH for the Fmoc-Tyr(tBu)-OH used 5 in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 19.8 mg. HPLC (method e):RT18.82 FAB-MS:483(M+H*) Example 45 10 Phe-Met-Tyr(3-tBu)-NH 2 Substituting Fmoc-Met-OH for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 24.3 mg. HPLC (method e):RT18.79 15 FAB-MS:515(M+H*) Example 46 Phe-His-Tyr(3-tBu)-NH 2 Substituting Fmoc-His(Boc)-OH for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated 20 to yield a TFA salt of the titled compound in 26.7 mg. HPLC (method e):RT16.78 FAB-MS:521(M+H*) Example 47 Phe-Trp-Tyr(3-tBu)-NH 2 25 Substituting Fmoc-Trp(Boc)-OH for the Fmoc-Tyr(tBu)-OH used in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 14.5 mg. HPLC (method e):RT20.76 RA4, - 79 - FAB-MS:570(M+H*) Example 48 Phe-Tiq-Tyr(3-tBu)-NH 2 Substituting Fmoc-Tiq-OH for the Fmoc-Tyr(tBu)-OH used 5 in Example 21, the procedure of Example 21 was repeated to yield a TFA salt of the titled compound in 23.7 mg. HPLC (method e):RT21.87 FAB-MS:543(M+H*) Example 49 10 N-(4-pyridylthioacetyl)-Phg-Tyr(3-tBu)-NH 2 A reaction vessel was charged with 91 mg (0.05 mmol) of Fmoc- 2,4 -dimethoxy- 4' - (carboxymethyloxy) -benzhydrylamine linked to Aminomethyl Resin (0.55 mmol/g); after being swelled with DMF, the resin was treated with piperidine to 15 remove Fmoc. Subsequently, Fmoc-Tyr(3-tBu)-OH was coupled by method 1. After filtering and washing with DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, Fmoc-Phg-OH was coupled by method 3. After filtering and washing with DMF, the resin was treated again 20 with piperidine to remove Fmoc. Subsequently, a mixture of 1.5 ml of DMF, 0.5 ml of NMM and 17 mg (0.1 mmol) of 4 pyridylthioacetic acid, as well as 23 mg (0.15 mmol) of HOBT and 25 ml (0.16 mmol) of DIC were added, followed by shaking for 2 hours to effect coupling. After the end of the 25 reaction, filtering and washing with DMF, DCM and methanol were performed and the resin was subsequently dried. Cleavage was also performed with 2 ml of 95% aqueous TFA. The reaction mixture was concentrated under reduced pressure -A48 and the residue was dissolved in 3 ml of methanol, followed by reconcentrating under reduced pressure to yield a TFA salt of the titled compound in 27.8 mg. HPLC (method a):RT17.55 5 FAB-MS:521(M+H*) Example 50 N-(1-benzocyclobutanecarbonyl)-Phg-Tyr(3-tBu)-NH 2 Substituting 1-benzocyclobutanecarboxylic acid for the 4-pyridylthioacetic acid used in Example 49, the procedure 10 of Example 49 was repeated (except that 1-benzocyclobutane carboxylic acid was coupled by method 3) to yield the titled compound in 23.8 mg as a mixture of diastereomers. HPLC (method a):RT23.43,23.68 FAB-MS:500(M+H*) 15 Example 51 N-(2-indolecarbonyl)-Phg-Tyr(3-tBu)-NH 2 Substituting 2-indolecarboxylic acid for the 1-benzo cyclobutanecarboxylic aid used in Example 50, the procedure of Example 50 was repeated to yield the titled compound in 20 8.0 mg. HPLC (method a):RT24.64 FAB-MS:513(M+H*) Example 52 Tyr-Phg-Tyr(3-tBu)-NH 2 25 A reaction vessel was charged with 91 mg (0.05 mmol) of Fmoc-2,4-dimethoxy-4'-(carboxymethyloxy)-benzhydrylamine linked to Aminomethyl Resin (0.55 mmol/g); after being swelled with DMF, the resin was treated with piperidine to - 81 remove Fmoc. Subsequently, Fmoc-Tyr(3-tBu)-OH was coupled by method 1. After filtering and washing with DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, Fmoc-Phg-OH was coupled by method 3. After 5 filtering and washing with DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, Fmoc-Tyr(tBu)-OH was coupled by method 3. After filtering and washing with DMF, the resin was treated again with piperidine to remove Fmoc. After the end of the reaction, washing was effected 10 with DCM and methanol and the resin was subsequently dried. Cleavage was performed with 2 ml of 95% aqueous TFA. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 3 ml of methanol, followed by reconcentrating under reduced pressure to yield a TFA salt 15 of the. titled compound in 26.2 mg. HPLC (method a):RT17.43 FAB-MS:533(M+H*) Example 53 Phg-Phg-Tyr(3-tBu)-NH 2 20 Substituting Fmoc-Phg-OH for the Fmoc-Tyr(tBu)-OH used in Example 52, the procedure of Example 52 was repeated to yield a TFA salt of the titled compound in 23.2 mg. HPLC (method a):RT18.42 FAB-MS:503(M+H*) 25 Example 54 Thi-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Thi-OH for the Fmoc-Tyr(tBu)-OH used RA4X in Example 52, the procedure of Example 52 was repeated to -82 yield a TFA salt of the titled compound in 27.4 mg. HPLC (method a):RT18.43 FAB-MS:523(M+H*) Example 55 5 Trp-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Trp(Boc)-OH for the Fmoc-Tyr(tBu)-OH used in Example 52, the procedure of Example 52 was repeated to yield a TFA salt of the titled compound in 20.9 mg. HPLC (method a):RT19.84 10 FAB-MS:556(M+H*) Example 56 His-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-His(Boc)-OH for the Fmoc-Tyr(tBu)-OH used in Example 52, the procedure of Example 52 was repeated 15 to yield a TFA salt of the titled compound in 14.4 mg. HPLC (method a):RT15.12 FAB-MS:507(M+H*) Example 57 N-((±)-3-phenylbutyryl)-Phg-Tyr(3-tBu)-NH 2 20 Substituting (±)-3-phenylbutyric acid for the 1 benzocyclobutanecarboxylic acid used in Example 50 and using 107 mg (0.05 mmol) of Rink Amide Resin (0.47 mmol/g) as a resin, the procedure of Example 50 was repeated (except that Fmoc-Phg-OH was coupled by method 1 and 3-phenylbutyric acid 25 by method 2) to yield the titled compound in 18.1 mg. HPLC (method a):RT25.19 FAB-MS:516(M+H*) Example 58 R441 - 83 4j, N-(2-biphenylcarbonyl)-Phg-Tyr(3-tBu)-NH 2 Substituting 2-biphenylcarboxylic acid for the 3 phenylbutyric acid used in Example 57, the procedure of Example 57 was repeated to yield the titled compound in 5 15.1 mg. HPLC (method a):RT26.23 FAB-MS:550(M+H*) Example 59 P-Ala-Phg-Tyr(3-tBu)-NH 2 10 A reaction vessel was charged with 45 mg (0.025 mmol) of Fmoc-2,4-dimethoxy-4'-(carboxymethyloxy)-benzhydrylamine linked to Aminomethyl Resin (0.55 mmol/g); after being swelled with DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, Fmoc-Tyr(3-tBu)-OH was coupled 15 by method 1. After filtering and washing with DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, Fmoc-Phg-OH was coupled by method 3. After washing with DMF, DCM and methanol, the resin was dried. The dried resin was transferred into a reaction vessel 20 of model ACT-496 MOS (product of Advanced ChemTech). After being swelled with DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, 0.5 ml of a mixture of Fmoc-P-Ala-OH, HOBT and DMF (Fmoc-1-Ala-OH in 0.050 mmol and HOBT in 0.075 mmol), as well as 0.25 ml of 25 DIC/DMF (DIC in 0.080 mmol) were added, followed by shaking for 2 hours. After filtering and washing with DMF, the resin was treated again with piperidine to remove Fmoc. After the end of the reaction, washing was effected with DCM - 84 * and cleavage was performed with 1 ml of 95% aqueous TFA. After recovering the reaction mixture by filtration, another 1 ml of 95% aqueous TFA was added, followed by shaking for 30 minutes. The filtrates were combined and concentrated 5 under reduced pressure, and the residue was dissolved in 3 ml of methanol, which was concentrated again to yield a TFA salt of the titled compound in 13.4 mg. HPLC (method e):RT16.72 FAB-MS: 441(M+H*) 10 Example 60 Aib-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Aib-OH for the Fmoc-P-Ala-OH used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 15.3 mg. 15 HPLC (method e):RT17.12 FAB-MS:455(M+H*) Example 61 Ile-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Ile-OH for the Fmoc-1-Ala-OH used in 20 Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 15.4 mg. HPLC (method e):RT18.25 FAB-MS:483 (M+H*) Example 62 25 Chg-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Chg-OH for the Fmoc-P-Ala-OH used in Example 59, the procedure of Example 59 was repeated to RA4/ yield a TFA salt of the titled compound in 12.2 mg. - 85 - HPLC (method e):RT19.61 FAB-MS:509(M+H*) Example 63 Cha-Phg-Tyr(3-tBu)-NH 2 5 Substituting Fmoc-Cha-OH for the Fmoc-$-Ala-OH used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 16.7 mg. HPLC (method e):RT21.34 FAB-MS:523(M+H*) 10 Example 64 Tle-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Tle-OH for the Fmoc-$-Ala-OH used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 14.9 mg. 15 HPLC (method e):RT18.02 FAB-MS:483(M+H*) Example 65 Asp-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Asp(OtBu)-OPfp for the Fmoc-1-Ala-OH 20 used in Example 59, the procedure of Example 59 was repeated (except that 0.25 ml of DIC/DMF was not added in coupling of Fmoc-Asp(OtBu)-OPfp) to yield a TFA salt of the titled compound in 18.1 mg. HPLC (method e):RT16.42 25 FAB-MS:485(M+H*) Example 66 Aad-Phg-Tyr(3-tBu)-NH 2 RAZ Substituting Fmoc-Aad(OtBu)-OH for the Fmoc-P-Ala-OH -86 used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 16.8 mg. HPLC (method e):RT16.79 FAB-MS:513(M+H*) 5 Example 67 Asn-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Asn-OH for the Fmoc-$-Ala-OH used in Example 59, the procedure of Example 59 was repeated to yield 17.2 mg of the titled compound. 10 HPLC (method e):RT16.17 FAB-MS: 484 (M+H*) Example 68 Gln-Phg-Tyr(3-tBu)

-NH

2 Substituting Fmoc-Gln-OPfp for the Fmoc-Asp(OtBu)-OPfp 15 used in Example 65, the procedure of Example 65 was repeated to yield a TFA salt of the titled compound in 15.9 mg. HPLC (method e):RT16.39 FAB-MS:498(M+H*) Example 69 20 Cit-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Cit-OH for the Fmoc--Ala-OH used in Example 59, the procedure of Example 59 was repeated to yield to yield a TFA salt of the titled compound in 15.3 mg. HPLC (method e):RT16.36 25 FAB-MS:527(M+H*) Example 70 Dab-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Dab(Boc)-OH for the Fmoc-1-Ala-OH - 7 - 87 used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 15.3 mg. HPLC (method e):RT15.28 FAB-MS:470 (M+H*) 5 Example 71 Lys-Phg-Tyr(3-tBu)

-NH

2 Substituting Fmoc-Lys(Boc)-OH for the Fmoc-$-Ala-OH used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 16.8 mg. 10 HPLC (method e):RT15.21 FAB-MS:498(M+H*) Example 72 Ser-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Ser(tBu)-OH for the Fmoc-P-Ala-OH 15 used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 15.4 mg. HPLC (method e):RT16.30 FAB-MS:457(M+H*) Example 73 20 Hse-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Hse(Trt)-OH for the Fmoc-$-Ala-OH used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 24.9 mg. HPLC (method e):RT16.50 25 FAB-MS:471(M+H*) Example 74 Thr-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Thr(tBu)-OH for the Fmoc-1-Ala-OH -88used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 15.5 mg. HPLC (method e):RT16.41 FAB-MS:471(M+H*) 5 Example 75 Abu-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Abu-OH for the Fmoc-p-Ala-OH used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 13.6 mg. 10 HPLC (method e):RT16.90 FAB-MS:455(M+H*) Example 76 Nva-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Nva-OH for the Fmoc-P-Ala-OH used in 15 Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 13.9 mg. HPLC (method e):RT17.79 FAB-MS:469(M+H*) Example 77 20 Met-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Met-OH for the Fmoc-p-Ala-OH used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 11.6 mg. HPLC (method e):RT18.09 25 FAB-MS:501(M+H*) Example 78 Pro-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Pro-OH-AcOEt for the Fmoc-@-Ala-OH -89 used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 14.8 mg. HPLC (method e):RT17.02 FAB-MS:467 (M+H*) 5 Example 79 Hyp-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Hyp-OH for the Fmoc-P-Ala-OH used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 11.2 mg. 10 HPLC (method e):RT16.54 FAB-MS:483(M+H*) Example 80 Tic-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Tic-OH for the Fmoc-P-Ala-OH used in 15 Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 16.1 mg. HPLC (method e):RT19.56 FAB-MS:529(M+H*) Example 81 20 Tiq-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Tiq-OH for the Fmoc-$-Ala-OH used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 14.7 mg. HPLC (method e):RT19.33 25 FAB-MS:529(M+H*) Example 82 2-Abz-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-2-Abz-OH for the Fmoc-$-Ala-OH used -90in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 15.2 mg. HPLC (method e):RT21.38 FAB-MS:489(M+H*) 5 Example 83 Hph-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-Hph-OH for the Fmoc-$-Ala-OH used in Example 59, the procedure of Example 59 was repeated to yield a TFA salt of the titled compound in 16.0 mg. 10 HPLC (method e):RT20.72 FAB-MS:531(M+H*) Example 84 N-(a-methylhydrocinnamoyl)-Phg-Tyr(3-tBu)-NH 2 Substituting a-methylhydrocinnamic acid for the Fmoc 15 p-Ala-OH used in Example 59, the procedure of Example 59 was repeated (except that prior to cleavage, no treatment for removing Fmoc was performed since this was unnecessary) to yield 15.2 mg of the titled compound. HPLC (method e):RT25.22 20 FAB-MS:516(M+H*) Example 85 N-(a-methylcinnamoyl)-Phg-Tyr(3-tBu)-NH 2 Substituting a-methylcinnamic acid for the a-methyl hydrocinnamic acid used in Example 84, the procedure of 25 Example 84 was repeated to yield 16.4 mg of the titled compound. HPLC (method e):RT26.18 FAB-MS:514(M+H*) -91 - Example 86 N-(3-quinolinecarbonyl)-Phg-Tyr(3-tBu)-NH 2 Substituting 3-quinolinecarboxylic acid for the a methyl-hydrocinnamic acid used in Example 84, the procedure 5 of Example 84 was repeated to yield 16.9 mg of the titled compound. HPLC (method e):RT20.73 FAB-MS:525(M+H*) Example 87 10 N-(3-furanacryloyl)-Phg-Tyr(3-tBu)-NH 2 Substituting 3-furanacrylic acid for the a methylhydro-cinnamic acid used in Example 84, the procedure of Example 84 was repeated to yield 8.2 mg of the titled compound. 15 HPLC (method e):RT23.08 FAB-MS:490(M+H*) Example 88 Phe-D-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-D-Phg-OH for the Fmoc-Phg-OH used in 20 Example 5 and using 182 mg (0.1 mmol) of Fmoc-2,4-dimethoxy 4'-(carboxymethyloxy)-benzhydrylamine linked to Aminomethyl Resin (0.55 mmol/g), the procedure of Example 5 was repeated (except that Fmoc-D-Phg-OH and Boc-Phe-OH were coupled by method 3) to yield a TFA salt of the titled compound in 25 15.4 mg. HPLC (method a):RT20.96 FAB-MS:517(M+H*) NMR(method gDMSO-d6): 8 1.27(9H,s), 2.57-3.06(4H,m), -92 - 4.28-4.35(2H,m), 5.63(lH,d,J=8Hz), 6.53(1H,d,J=8Hz), 6.70(1H,d,J=8Hz), 6.79(2H,d,J=7Hz), 7.00-7.29(11H,m), 7.51(1H,s), 8.20(3H,brs), 8.71(lH,d,J=8Hz), 9.07(1H,s), 9.13(lH,d,J=8Hz) 5 Example 89 Phe-N-Me-Val-Tyr( 3-tBu) -NH 2 (1) Synthesis of Z-Tyr(3-tBu)-NH 2 To a solution of 15.3 mg (39.8 mmol) of Z-Tyr(3-tBu) OMe in 100 ml of 1,4-dioxane, 100 ml of 2 N aqueous sodium 10 hydroxide was added and the mixture was stirred at room temperature for 2 hours and a half. The reaction mixture was rendered acidic by addition of 2 N hydrochloric acid, extracted with ethyl acetate, washed first with water, then with saturated brine. The organic layer was dried with 15 anhydrous sodium sulfate and the solvent was distilled off under reduced pressure; the resulting residue was dissolved in 100 ml of DMF, followed by addition of NMM and ethyl chloroformate in respective amounts of 4.77 mg (43.4 mmol) and 4.15 ml (43.4 mmol) at -15 0 C. The reaction mixture was 20 stirred with bubbling of ammonia gas for one hour and a half, and then left to stand at room temperature, diluted with ethyl acetate, washed first with water, then with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the 25 resulting residue was subjected to silica gel column chromatography (eluting solvent; methylene chloride:methanol = 100:1) to give Z-Tyr(3-tBu)-NH 2 in 10.9 g (74%). (2) Synthesis of Tyr(3-tBu)-NH2 -) - 93 - To a solution of 9.89 g (26.7 mmol) of Z-Tyr(3-tBu)

NH

2 in 350 ml of methanol, 3.5 g of 10% palladium carbon was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 10 hours. After filtering, the 5 filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent; methylene chloride:methanol = 20:1) to yield Tyr(3-tBu)-NH 2 in 5.11 g (81%). NMR(method gCDCl 3 ): 6 1.40(9H,s), 2.64(1H,dd,J=9.6,13.9Hz), 10 3.18(1H,dd,J=4.0,13.9Hz), 3.49(lH,s), 3.58(1H,dd,J=4.0,9.6Hz), 5.45(lH,brs), 6.65(1H,d,J=7.9Hz), 6.92(1H,dd,J=2/0,12.OHz), 7.10(lH,d,J=2.OHz), 6.94(1H,d,6.6Hz), 7.2-7.4(8H,m), 7.7-7.9(2H,m), 8.46(1H,d,7.6Hz), 9.06(lH,d) 15 (3) Synthesis of Z-N-Me-Val-Tyr(3-tBu)-NH 2 To a solution of 400 mg (1.52 mmol) of Z-N-Me-Val-OH, 300 mg (1.27 mmol) of Tyr(3-tBu)-NH 2 and 230 mg (1.52 mmol) of HOBT in 7 ml of DMF, 0.24 ml (1.52 mmol) of DIC was added dropwise under cooling with ice and the mixture was stirred 20 at room temperature for 15 hours and a half. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column 25 chromato-graphy (eluting solvent consisting of methylene chloride, methanol and aqueous ammonia at a ratio of 100:3:1) to give 810 mg of Z-N-Me-Val-Tyr(3-tBu)-NH 2 (4) Synthesis of Boc-Phe-N-Me-Val-Tyr(3-tBu)-NH 2 - 94 - A mixture of 810 mg of Z-N-Me-Val-Tyr(3-tBu)-NH 2 and 300 mg of 10% palladium carbon in 50 ml of methanol was stirred under a hydrogen stream for 13 hours and a half. The reaction mixture was filtered and the filtrate was 5 distilled off under reduced pressure. To a solution in DMF (12 ml) of 470 mg (1.35 mmol) of the resulting N-Me-Val Tyr(3-tBu)-NH 2 , 390 mg (1.48 mmol) of Boc-Phe-OH and 230 mg (1.48 mmol) of HOBT, 0.23 ml (1.48 mmol) of DIC was added dropwise under cooling with ice and the mixture was stirred 10 at room temperature for 13 hours and a half. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column 15 chromatography (eluting solvent consisting of methylene chloride, methanol and aqueous ammonia at a ratio of 100:3:1) to give Boc-Phe-N-Me-Val-Tyr(3-tBu)-NH 3 in 380 mg (47%). (5) Synthesis of Phe-N-Me-Val-Tyr(3-tBu)-NH 2 20 A solution of 380 mg (0.638 mmol) of Boc-Phe-N-Me-Val Tyr(3-tBu)-NH 2 in 15 ml of TFA was stirred at room temperature for one hour and a half. The reaction solution was concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate and washed first with 25 saturated aqueous NaHCO 3 , then with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; thereafter, the RA& resulting residue was subjected to silica gel column - 95 4u chromato-graphy (eluting solvent consisting of methylene chloride, methanol and aqueous ammonia at a ratio of 100:10:1) to give Phe-N-Me-Val-Tyr(3-tBu)-NH 2 in 240 mg (76%) 5 FAB-MS:497(M+H*) NMR(method gCDCl 3 ):b 0.74(2H,d,J=6.6Hz), 0.79(lH,d,J=6.6Hz), 0.89(lH,d,J=6.6Hz), 0.92(2H,d,J=6.6Hz), 1.36(3H,s), 1.38(6H,s), 2.27-2.35(lH,m), 2.71(2H,s), 2.81(lH,s), 2.77-3.19(4H,m), 3.56-3.61(2/3H,m), 3.80 10 3.90(1/3H,m), 3.95(2/3H,d,J=10.9Hz), 4.46(1/3H,d,J=11.2Hz), 4.55-4.65(1/3H,m), 4.70-4.85(2/3H,m), 6.60-7.40(8H,m) Example 90 N-(a-methylhydrocinnamoyl)-N-Me-D-Phg-Tyr(3-tBu)-NH 2 (1) Synthesis of Z-N-Me-Phg-Tyr(3-tBu)-NH 2 15 To a solution of 3.28 g (11.0 mmol) of Z-N-Me-Phg-OH, 2.16 g (9.17 mmol) of Tyr(3-tBu)-NH 2 and 1.40 g (9.17 mmol) of HOBT in 60 ml of DMF, 1.42 ml (9.17 mmol) of DIC was added dropwise under cooling with ice and the mixture was stirred for 4 hours under cooling with ice. The reaction 20 mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of methylene 25 chloride, methanol and aqueous ammonia at a ratio of 100:5:1) to give Z-N-Me-Phg-Tyr(3-tBu)-NH2 in 4.03 g (85%). (2) Synthesis of N-Me-D-Phg-Tyr(3-tBu)-NH 2 A mixture of Z-N-Me-Phg-Tyr(3-tBu)-NH2 (4.03 g) and - 96 R

*-L

10% palladium carbon (2.0 g) in methanol (200 ml) was stirred in a hydrogen atmosphere for 4 hours. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure; the resulting residue was subjected 5 to silica gel column chromatography (eluting solvent consisting of methylene chloride, methanol and aqueous ammonia at a ratio of 100:5:1) to give N-Me-Phg-Tyr(3-tBu)

NH

2 in 1.48 g (50%) and of N-Me-D-Phg-Tyr(3-tBu)-NH 2 in 920 mg (31%). 10 (3) Synthesis of N-(a-methylhydrocinnamoyl)-N-Me-D-Phg Tyr(3-tBu)-NH 2 To a solution of a-methylhydrocinnamic acid (141 mg) in 10 ml of thionyl chloride, DMF (0.01 ml) was added and the mixture was stirred at 80 0 C for 1.5 hours. The reaction 15 mixture was distilled off under reduced pressure and the resulting residue was dissolved in methylene chloride; the solution was added to a solution of 300 mg (0.78 mmol) of N Me-D-Phg-Tyr(3-tBu)-NH 2 and 260 mg (3.13 mmol) of NaHCO 3 in 6 ml of H 2 0 and the mixture was stirred at room temperature 20 for 45 minutes. The reaction mixture was diluted with ethyl acetate and washed first with water, then with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column 25 chromatography (eluting solvent; ethyl acetate:n-hexane = 4:1) to yield N-(a-methylhydrocinnamoyl)-N-Me-D-Phg-Tyr(3 tBu)-NH 2 in 210 mg (51%). EI-MS:529(M*) 9- -97 4-U NMR(method gCDCl 3 ):b 1.18(3/2H,d,J=6.3Hz), 1.25(3/2H,d,J=6.9Hz), 1.35(9H,s), 2.64-3.14(6H,m), 2.73(3/2H,s), 2.81(3/2H,s), 4.67(lH,dd,J=7.4,14.OHz), 5.09(1/2H,s), 5.38(lH,brd,J=8.9Hz), 5.47(1/2H,s), 5 5.75(1/2H,s), 5.77(1/2H,s), 5.86(1/2H,s), 6.06(1/2H,brd,J=7.9Hz), 6.48-6.72(2H,m),6.86-7.00(2H,m), 7.14-7.34(9H,m) Example 91 Phe-Val-N-Me-Tyr(3-tBu)-NH 2 10 (1) Synthesis of Z-Phe(3-tBu-4-benzyloxy)-OMe To a solution of 1.05 g (2.73 mmol) of Z-Tyr(3-tBu) OMe in 10 ml of DMF, 120 mg (3.00 mmol) of sodium hydride (60% in oil) and 0.357 ml (3.00 mmol) of benzyl bromide were added under cooling with ice and the mixture was stirred for 15 4 hours. After neutralization with saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate and washed first with water, then with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; 20 the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 1:5) to give Z-Phe(3-tBu-4-benzyloxy)-OMe in 688 mg (53%). (2) Synthesis of Z-N-Me-Phe(3-tBu-4-benzyloxy)-OMe To a solution of 680 mg (1.43 mmol) of Z-Phe(3-tBu-4 25 benzyloxy)-OMe in 8 ml of DMF, 74.4 mg (1.86 mmol) of sodium hydride (60% in oil) and 0.134 ml (2.15 mmol) of methyl iodide were added under cooling with ice and the mixture was RA4 stirred for 1 hour. After neutralization with saturated -98aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate and washed first with water, then with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced 5 pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n hexane = 1:4) to give Z-N-Me-Phe(3-tBu-4-benzyloxy)-OMe in 659 mg (94%). (3) Synthesis of N-Me-Tyr(3-tBu)-NH 2 10 To a solution of 655 mg (1.34 mmol) of Z-N-Me-Phe(3 tBu-4-benzyloxy)-OMe in 8 ml of 1,4-dioxane, 2 ml of 2 N aqueous sodium hydroxide was added under cooling with ice and the mixture was stirred at room temperature for 1 hour. The reaction mixture was rendered acidic by addition of 2 N 15 hydrochloric acid, extracted with chloroform and washed first with water, then with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure; the resulting residue was dissolved in 5 ml of DMF and 0.183 ml 20 (1.66 mmol) of NMM and 0.159 ml (1.66 mmol) of ethyl chloroformate were added to the solution at -15 0 C, followed by stirring for 20 minutes. The reaction mixture was stirred with bubbling of ammonia gas for additional 30 minutes, left to stand at room temperature, diluted with 25 ethyl acetate and washed first with water, then with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure; the resulting residue was dissolved in 7 -99ml of methanol and after addition of 20% palladium hydroxide on carbon (100 mg), the mixture was stirred in a hydrogen atmosphere at room temperature for 4 hours. After filtering, the filtrate was concentrated under reduced pressure to give 5 N-Me-Tyr(3-tBu)-NH 2 in 314 mg (94%). (4) Synthesis of Boc-Val-N-Me-Tyr(3-tBu)-NH 2 To a solution of 120 mg (0.480 mmol) of N-Me-Tyr(3 tBu)-NH 2 , 156 mg (0.718 mmol) of Boc-Val-OH and 110 mg (0.718 mmol) of HOBT in 2 ml of DMF, 0.111 ml (0.718 mmol) 10 of DIC was added under cooling with ice and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO 3 , then with water, and finally with saturated brine. The organic layer was dried with anhydrous 15 magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 2:1) to give Boc-Val-N-Me-Tyr(3-tBu)-NH 2 in 147 mg (68%). (5) Synthesis of Z-Phe-Val-N-Me-Tyr(3-tBu)-NH 2 20 To a solution of 146 mg (0.325 mmol) of Boc-Val-N-Me Tyr(3-tBu)-NH 2 in 2 ml of methylene chloride, 1 ml of TFA was added and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure. To a solution of the resulting TFA salt of Val-N 25 Me-Tyr(3-tBu)-NH 2 in 2 ml of DMF, 0.1 ml of TEA, 219 mg (0.348 mmol) of Z-Phe-ONp and 93.5 mg (0.765 mmol) of DMAP were added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl - 100 acetate and washed first with saturated aqueous NaHCO 3 , then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue 5 was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 1:1) to give Z-Phe-Val-N Me-Tyr(3-tBu)-NH 2 in 189 mg (92%). (6) Synthesis of Phe-Val-N-Me-Tyr(3-tBu)-NH 2 To a solution of 183 mg (0.290 mmol) of Z-Phe-Val-N 10 Me-Tyr(3-tBu)-NH 2 in 3 ml of methanol, 100 mg of 10% palladium carbon was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 5 hours. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica 15 gel column chromatography (eluting solvent; ethyl acetate:methanol = 10:1) to yield Phe-Val-N-Me-Tyr(3-tBu)

NH

2 in 108 mg (75%). NMR(method gCDCl 3 ): 8 0.69(3H,dd,J=6.9,17.8Hz), 0.89(3H,dd,J=6.9,14.5Hz), 1.36(9/2H,s), 1.39(9/2H,s), 20 2.67(lH,dd,J=9.6,13.5Hz), 2.78-2.94(lH,m), 2.97(3/2H,s), 3.09(3/2H,s), 3.12-3.40(2H,m), 3.59(1H,ddd,J=3.6,9.3,10.2Hz), 4.34-4.42(1/2H,m), 4.68(1/2H,ddJ=6.6,11.lHz), 4.79(1/2H,dd,J=7.9,8.9Hz), 5.18-5.26(1/2H,m), 5.35(1/2H,brs), 5.49(1/2H,brs), 6.60(1H,dd,J=7.9,12.2Hz), 25 6.86(lH,ddd,J=1.6,6.3,6.3Hz), 7.06(1H,s), 7.16-7.34(5H,m), 7.76(1/2H,brs), 7.85(1/2H,d,J=8.9Hz), 7.95(1/2H,d,J=7.9Hz) Example 92 Phe-Phg-Tyr(3-tBu)-NHMe - 101 J (1) Synthesis of Tyr(3-tBu)-NHMe To a solution of 10.6 g (42.0 mmol) of Tyr(3-tBu)-OMe in 80 ml of methanol, 80 ml of a solution of 40% methylamine in methanol and 0.41 g of sodium cyanide were added and the 5 mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in methylene chloride, followed by washing first with water, then with saturated brine. The organic layer was dried with anhydrous sodium 10 sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 20:1:0.1) to give Tyr(3-tBu)-NHMe in 7.3 g (70%). 15 (2) Synthesis of Phe-Phg-Tyr(3-tBu)-NHMe To a solution of 150 mg (0.597 mmol) of Boc-Phg-OH, 136 mg (0.542 mmol) of Tyr(3-tBu)-NHMe, 110 mg (0.813 mmol) of HOBT and 99 mg (0.813 mmol) of DMAP in 3 ml of DMF, 156 mg (0.813 mmol) of WSCI'HCl was added under cooling with ice 20 and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO,, then with water, and finally with saturated brine. After drying the organic layer with anhydrous magnesium sulfate, the solvent was 25 distilled off under reduced pressure and the resulting residue was dissolved in 3 ml of methylene chloride, followed by addition of 2 ml of TFA. After being stirred at room temperature for 15 minutes, the reaction mixture was - 102 distilled off under reduced pressure and the resulting residue was dissolved in methylene chloride, followed by washing with saturated aqueous NaHCO 3 , then with saturated brine. The organic layer was dried with anhydrous magnesium 5 sulfate and the solvent was distilled off under reduced pressure to give a TFA salt of Phg-Tyr(3-tBu)-NHMe. To a solution of 0.44 g of this TFA salt, 158 mg (0.597 mmol) of Boc-Phe-OH, 110 mg (0.813 mmol) of HOBT and 165 mg (1.36 mmol) of DMAP in 5 ml of DMF, 156 mg (0.813 mmol) of 10 WSCI'HCl was added under cooling with ice and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO 3 , then with water and finally with saturated brine. The organic layer was dried with anhydrous 15 magnesium sulfate and the solvent was distilled off under reduced pressure; the resulting residue was dissolved in 4 ml of methylene chloride and after adding 4 ml of TFA, the mixture was stirred at room temperature for 40 minutes. The reaction mixture was distilled off under reduced pressure 20 and the resulting residue was dissolved in methylene chloride, followed by washing first with saturated aqueous NaHCO,, then with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected 25 to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 20:1:0.1) to yield Phe-Phg-Tyr(3-tBu)-NHMe in 158 mg (55% in four steps).

AZ

1 - 103 - FAB-MS:531(M+H*) NMR(method gDMSO-d6):5 1.30(9H,s), 1.78(lH,brs), 2.6-3.0(4H,m), 3.17(3H,d,J=4.6Hz), 3.45-3.50(lH,m), 4.05-4.15(lH,m), 4.3-4.4(lH,m), 5.48(1H,s), 5 6.64(1H,d,J=8.3Hz), 6.81(lH,dd,J=2.0,8.3Hz), 6.97(lH,d,J=2.0Hz), 7.17-7.28(10H,m), 7.71(lH,m), 8.45(lH,brs), 8.48(1H,d,J=8.2Hz), 9.11(1H,s) Example 93 Phe-Apc-Tyr(3-tBu)-NHMe 10 (1) Synthesis of Z-Apc-Tyr(3-tBu)-NHMe To a solution of 206 mg (0.877 mmol) of Z-Apc-OH, 219 mg (0.876 mmol) of Tyr(3-tBu)-NHMe, 178 mg (1.32 mmol) of HOBT and 214 mg (1.75 mmol) of DMAP in 3 ml of DMF, 252 mg (1.31 mmol) of WSCI'HCl was added and the mixture was 15 stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO,, then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; 20 the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 1:1) to give 205 mg (50%) of Z-Apc-Tyr(3-tBu)-NHMe. (2) Synthesis of Boc-Phe-Apc-Tyr(3-tBu)-NHMe To a solution of 201 mg (0.430 mmol) of Z-Apc-Tyr(3 25 tBu)-NHMe in 3 ml of methanol, 100 mg of 10% palladium carbon was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 hours. After filtering, ,- RA the filtrate was distilled off under reduced pressure and -104 9\/r nO' the resulting residue was dissolved in 3 ml of DMF; to the solution under cooling with ice, 228 mg (0.859 mmol) of Boc Phe-OH, 380 mg (0.859 mmol) of BOP and 0.472 ml (4.30 mmol) of NMM were added and the mixture was stirred at room 5 temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO 3 , then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting 10 residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate = 1:1) to give Boc Phe-Apc-Tyr(3-tBu)-NHMe in 108 mg (43%). (3) Synthesis of Phe-Apc-Tyr(3-tBu)-NHMe To a solution of 103 mg (0.178 mmol) of Boc-Phe-Apc 15 Tyr(3-tBu)-NHMe in 2 ml of methylene chloride, 1 ml of TFA was added. After being stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in methylene chloride, followed by washing first with saturated 20 aqueous NaHCO,, then with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous 25 ammonia at a ratio of 10:1:0.1) to yield Phe-Apc-Tyr(3-tBu) NHMe in 68.4 mg (80%). NMR(method gCDCl 3 ):8 1.10-1.40(4H,m), 1.36(9H,s), 2.83(3H,d,J=4.6Hz), 2.80-3.15(2H,m), 3.30-3.70(3H,m), -z - 105 *

'I

4.91(1H,dd,J=7.6,9.7Hz), 5.56(lH,brs), 6.56(lH,d,J=7.9Hz), 6.73(lH,brs), 6.89(1H,dd,J=2.0,7.9Hz), 7.02(lH,d,J=2.OHz), 7.10-7.40(6H,m) Example 94 5 Phe-Ahc-Tyr(3-tBu)-NHMe (1) Synthesis of Z-Ahc-Tyr(3-tBu)-NHMe To a solution of 400 mg (1.44 mmol) of Z-Ahc-OH, 360 mg (1.44 mmol) of Tyr(3-tBu)-NHMe, 389 mg (2.88 mmol) of HOBT and 351 mg (2.88 mmol) of DMAP in 5 ml of DMF, 552 mg 10 (2.88 mmol) of WSCI'HCl was added under cooling with ice and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO 3 , then with water and finally with saturated brine. The organic layer was 15 dried with magnesium sulfate and, concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n hexane = 1:2) to give Z-Ahc-Tyr(3-tBu)-NHMe in 203 mg (28%). (2) Synthesis of Z-Phe-Ahc-Tyr(3-tBu)-NHMe 20 To 192 mg (0.377 mmol) of Z-Ahc-Tyr(3-tBu)-NHMe in a mixture of methanol (2 ml) and 1,4-dioxane (1 ml), 100 mg of 10% palladium carbon was added and the mixture was stirred overnight in a hydrogen atmosphere at room temperature. After filtering, the filtrate was concentrated under reduced 25 pressure and the resulting residue was dissolved in 2 ml of DMF; to the solution under cooling with ice, 190 mg (0.452 mmol) of Z-Phe-ONp and 69.1 mg (0.566 mmol) of DMAP were added and the mixture was stirred overnight at room - 106 L)zA6 temperature. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO 3 , then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and 5 concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 2:1) to give Z-Phe-Ahc Tyr(3-tBu)-NHMe in 217 mg (88%). (3) Synthesis of Phe-Ahc-Tyr(3-tBu)-NHMe 10 To a solution of 192 mg (0.320 mmol) of Z-Phe-Ahc Tyr(3-tBu)-NHMe in 2 ml of methanol, 100 mg of 10% palladium carbon was added and the mixture was stirred overnight in a hydrogen atmosphere at room temperature. After filtering, the filtrate was concentrated under reduced pressure and the 15 resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol = 10:1) to yield Phe-Ahc-Tyr(3-tBu)-NHMe in 136 mg (81%). EI-MS: 523(M*+1) NMR(method gCDCl 3 ): 8 1.00-1.90(10H,m), 1.37(9H,s), 20 2.64-2.80(lH,m), 2.75(3H,d,J=4.6Hz), 2.90-3.15(2H,m), 3.22-3.40(2H,m), 4.52-4.62(lH,m), 6.19(lH,d,J=8.3Hz), 6.77(lH,d,J=7.9Hz), 6.83(1H,d,J=7.9Hz), 6.98(1H,s), 7.12-7.38(7H,m), 7.96(lH,s) Example 95 25 N-acetyl-transHyp(O-benzyl)-Tyr(3-tBu)-NHMe (1) Synthesis of Boc-transHyp(O-benzyl)-Tyr(3-tBu)-OMe To a solution of 300 mg (0.933 mmol) of Boc transHyp(O-benzyl)-OH, 281 mg (1.12 mmol) of Tyr(3-tBu)-OMe, -107 - 189 mg (1.40 mmol) of HOBT and 171 mg (1.40 mmol) of DMAP in 7 ml of DMF, 268 mg (1.40 mmol) of WSCI-HCl was added under cooling with ice and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted 5 with ethyl acetate and washed first with saturated aqueous NaHCO 3 , then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography 10 (eluting solvent; ethyl acetate:n-hexane = 1:1) to give Boc transHyp(O-benzyl)-Tyr(3-tBu)-OMe in 505 mg (97%). (2) Synthesis of transHyp(O-benzyl)-Tyr(3-tBu)-NHMe To a solution of 500 mg (0.901 mmol) of Boc transHyp(O-benzyl)-Tyr(3-tBu)-OMe in 5 ml of methanol, 5 ml 15 of a solution of 40% methylamine in methanol and 10 mg of sodium cyanide were added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in methylene chloride, followed by 20 washing first with water, then with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure; the resulting residue was dissolved in 5 ml of methylene chloride and 3 ml of TFA was added. After being stirred at 25 room temperature for 15 minutes, the reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in methylene chloride, followed by washing first with saturated aqueous NaHCO,, then with - 108 saturated brine. The organic layer was dried with anhydrous magnesium and the solvent was distilled off under reduced pressure to transHyp(O-benzyl)-Tyr(3-tBu)-NHMe in give 380 mg (93%). 5 (3) Synthesis of N-acetyl-transHyp(O-benzyl)-Tyr(3-tBu)-NHMe To a solution of 104 mg (0.229 mmol) of transHyp(O benzyl)-Tyr(3-tBu)-NHMe in 1 ml of methylene chloride, 1 ml of pyridine and 0.024 ml (0.344 mmol) of acetyl chloride were added under cooling with ice and the mixture was 10 stirred for 40 minutes. The reaction mixture was diluted with methylene chloride and washed with saturated aqueous NaHCO 3 ; then, the organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was subjected to 15 silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 20:1:0.1) to yield N-acetyl-transHyp(O-benzyl)-Tyr(3-tBu) NHMe in 94 mg (83%). FAB-MS:496(M+H*) 20 NMR(method gCDCl 3 ): 5 1.36(9H,s), 1.93(3H,s), 2.23(2H,dd,J=7.2,6.9Hz), 2.74(3H,d,J=5.OHz), 2.98(lH,dd,J=6.9,14Hz), 3.10(1H,dd,J=6.5,14Hz), 3.50(2H,m), 4.18(lH,m), 4.4-4.6(4H,m), 5.88(1H,s), 6.28(lH,m), 6.60(lH,d,J=7.9Hz), 6.62(1H,s), 25 6.81(1H,dd,J=2.0,5.2Hz), 6.99(lH,d,J=2.OHz), 7.26-7.38(5H,m) Example 96 Phe-Cha-Phe(3-tBu)-NH 2 - 109 - (1) Synthesis of N-[bis(methylthio)methylene]-3-t butylphenyl-alanine To a solution of 1.78 g (15.8 mmol) of potassium t butoxide in 30 ml of THF, a solution of 3.28 g (15.8 mmol) 5 of N-[bis(methylthio)-methylene]glycine ethyl ester (Angew. Chem. Internat. Edit., 14, 426 (1975)) and 2.39 g (10.5 mmol) of 3-t-butylbenzyl bromide (Eur. J. Med. Chem., 23, 477 (1988)) in 10 ml of THF was added at -78 0 C and the mixture was stirred at room temperature for 1 hour. Under 10 cooling with ice, 10 ml of water was added, then 5 ml of 2 N aqueous sodium hydroxide was added and the mixture was stirred at room temperature for another 1 hour. Under cooling with ice, 2 N hydrochloric acid was added to the reaction mixture to render it acidic; the reaction mixture 15 was extracted with chloroform and washed first with water, then with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate) to 20 give N-[bis(methylthio)methylene]-3-t-butylphenylalanine in 577 mg (16%). (2) Synthesis of Phe(3-tBu)-NH 2 To a solution of 492 mg (1.51 mmol) of N-[bis-(methyl thio)methylene]-3-t-butylphenylalanine in 5 ml of DMF, 0.183 25 ml (1.66 mmol) of NMM and 0.159 ml (1.66 mmol) of ethyl chloroformate were added at -15 0 C and the mixture was stirred for 30 minutes. The reaction mixture was stirred with bubbling of ammonia gas for another 30 minutes, left to -110 stand at room temperature, diluted with ethyl acetate and washed first with water, then with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure; the 5 resulting residue was dissolved in 3 ml of 1,4-dioxane and, after adding 1 ml of 2 N hydrochloric acid, the solution was stirred at room temperature for 3 days. Under cooling with ice, the solution was neutralized with saturated aqueous NaHCO 3 , extracted with chloroform, and washed first with 10 water, then with saturated brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol = 10:1) to give Phe(3-tBu)-NH 2 in 210 mg (63%). 15 EI-MS:221(M*+1) NMR(g method,CDCl): 1.32(9H,s), 2.69(lH,dd,J=9.6,13.5Hz), 3.29(lH,dd,J=4.0,13.5Hz), 3.62(lH,dd,J=4.0,9.6Hz), 5.38(lH,brs), 7.00-7.38(4H,m) (3) Synthesis of Boc-Cha-Phe(3-tBu)-NH 2 20 To a solution of 205 mg (0.932 mmol) of Phe(3-tBu)-NH 2 , 351 mg (1.21 mmol) of Boc-Cha-OH, 164 mg (1.21 mmol) of HOBT and 148 mg (1.21 mmol) of DMAP in 4 ml of DMF, 232 mg (1.21 mmol) of WSCI-HCl was added under cooling with ice and the mixture was stirred at room temperature for 1 hour. The 25 reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO 3 , then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under NRA - 111 reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 2:1) to give Boc-Cha-Phe(3-tBu)-NH 2 in 326 mg (74%). 5 (4) Synthesis of Z-Phe-Cha-Phe(3-tBu)-NH 2 To a solution of 322 mg (0.681 mmol) of Boc-Cha-Phe(3 tBu) -NH 2 in 2 ml of methylene chloride, 1 ml of TFA was added and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure 10 to give a TFA salt of Cha-Phe(3-tBu)-NH 2 ; to a solution of the TFA salt in 2 ml of DMF, 0.1 ml of TEA, 343 mg (0.817 mmol) of Z-Phe-ONp and 125 mg (1.02 mmol) of DMAP were added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and 15 washed first with saturated aqueous NaHCO 3 , then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; 20 chloroform:methanol = 10:1) to give Z-Phe-Cha-Phe(3-tBu)-NH 2 in 192 mg (43%). (5) Synthesis of Phe-Cha-Phe(3-tBu)-NH 2 To a solution of 188 mg (0.287 mmol) of Z-Phe-Cha Phe(3-tBu)-NH 2 in 3 ml of methanol, 100 mg of 10% palladium 25 carbon was added and the mixture was stirred overnight in a hydrogen atmosphere at room temperature. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column - 112 * - C chromatography (eluting solvent, chloroform:methanol = 10:1) to yield Phe-Cha-Phe(3-tBu)-NH 2 in 69.0 mg (46%). EI-MS:520(M*) NMR(method gCDCl 3 ): 8 0.80-1.75(13H,m)1.29(9H,s), 5 2.70(lH,dd,J=8.6,13.5Hz), 3.00-3.28(3H,m), 3.40(1H,dd,J=4.0,8.6Hz), 4.18-4.32(lH,m), 4.66(lH,dd,J=6.9,6.9Hz), 5.32(lH,brs), 6.20(lH,brs), 6.50(lH,d,J=7.9Hz), 7.01(lH,d,J=6.3Hz), 7.12-7.38(7H,m), 7.58(lH,d,J=6.9Hz) 10 Example 97 N-(benzylaminocarbonyl)-N-Me-D-Phg-Tyr(3-tBu)-NH 2 To a solution of benzylamine (27 mg) in methylene chloride (2 ml), 74 mg (0.25 mmol) of triphosgene and 0.04 ml of DIEA were added under cooling with ice and the 15 mixture was stirred at room temperature for 45 minutes. The reaction mixture was distilled off under reduced pressure and the resulting residue was dissolved in methylene chloride and added to a solution of 100 mg (0.26 mmol) of N-Me-D-Phg-Tyr(3-tBu)-NH 2 and 84 mg (0.99 mmol) of 20 NaHCO 3 in 2 ml of H 2 0, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with methylene chloride and washed first with water, then with saturated brine. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off 25 under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 100:10:1) to yield N-(benzylamino-carbonyl)-N-Me-D -113 W

'N'

Phg-Tyr(3-tBu)-NH 2 in 70 mg (54%). EI-MS:498(M*-18) NMR(method gCDCl 3 ): 6 1.34(9H,s), 2.72(3H,s), 2.93(lH,dd,J=7.6,14.3Hz), 3.05(lH,dd,J=5.8,14.3Hz), 5 4.40(2H,brd,J=5.3Hz), 4.68(lH,dd,J=7.6,13.9Hz), 4.99 5.12(lH,m), 5.70-5.38(lH,m), 5.40(lH,brs), 6.14-6.32(2H,m), 6.55(lH,d,J=7.9Hz), 6.66(lH,dd,J=1.8,8.lHz), 6.97(1H, d,J=10.2Hz), 7.07-7.16(lH,m), 7.25-7.36(10H,m) Example 98 10 N-(benzyloxycarbonyl)-Phg-Tyr(3-tBu)-NHMe (1) Synthesis of Z-Phg-Tyr(3-tBu)-OMe To a solution of Z-Phg-OSu (640 mg) in DMF (10 ml), 463 mg (1.84 mmol) of Tyr(3-tBu)-OMe and 408 mg (3.34 mmol) of DMAP were added and the mixture was stirred at room 15 temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO,, then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting 20 residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 1:1) to give Z Phg-Tyr(3-tBu)-OMe in 905 mg (quantitative). (2) Synthesis of N-(benzyloxycarbonyl)-Phg-Tyr(3-tBu)-NHMe To a solution of 900 mg (1.73 mmol) of Z-Phg-Tyr(3 25 tBu)-OMe in 10 ml of methanol, 10 ml of a solution of 40% methylamine in methanol and 10 mg of sodium cyanide were added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under - 114 reduced pressure and the resulting residue was dissolved in methylene chloride, followed by washing first with water, then with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced 5 pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n hexane = 2:1) to yield N-(benzyloxycarbonyl)-Phg-Tyr(3-tBu) NHMe in 737 mg (82%). FAB-MS: 518 (M+H*) 10 NMR(method gDMSO-d6): 8 1.30(9H,s), 2.57(3H,d,J=4.3Hz), 2.5-2.9(2H,m)3.30(lH,d,J=5.3Hz), 4.0-4.1(lH,m), 4.2 4.4(lH,m), 5.03(2H,s), 5.28(lH,d,J=8.5Hz), 6.5-6.8(2H,m), 6.94(1H,d,6.6Hz), 7.2-7.4(8H,m), 7.7-7.9(2H,m), 8.46(lH,d,7.6Hz), 9.06(lH,d) 15 Example 99 N-(benzyloxycarbonyl)-N-Me-Val-Tyr(3-tBu)-NH 2 To a solution of 1.70 g (7.20 mmol) of Tyr(3-tBu)-NH 2 , 2.10 g (7.92 mmol) of Z-N-Me-Val-OH, 1.07 g (7.92 mmol) of HOBT and 970 mg (7.94 mmol) of DMAP in 20 ml of DMF, 1.52 g 20 (7.93 mmol) of WSCI-HCl was added under cooling with ice and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO 3 , then with water and finally with saturated brine. The organic layer was 25 dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl RA41 acetate:n-hexane = 2:1) to yield N-(benzyloxycarbonyl)-N-Me - 115 rn D Val-Tyr(3-tBu)-NH 2 in 3.30 g (95%). FAB-MS: 484 (M+H*) NMR(method gCDCl 3 ): 8 0.83(3H,d,J=6.6Hz), 0.88(3H,d,J=6.6Hz), 1.36(9H,s), 2.15-2.30(lH,m), 2.75(3H,s), 5 2.80-3.05(2H,m), 4.02(1H,d,J=10.9Hz), 4.52-4.64(lH,m), 5.13(2H,s), 5.39(lH,brs), 5.88(lH,brs), 6.40-6.84(3H,m), 7.08(1H,s), 7.28-7.42(5H,m) Example 100 N-((R)-3-phenylbutyryl)-Phg-Tyr(3-tBu)-NH 2 10 A reaction vessel was charged with 182 mg (0.1 mmol) of Fmoc- 2,4 -dimethoxy- 4- (carboxymethyloxy) -benzhydrylamine linked to Aminomethyl Resin (0.55 mmol/g); after being swelled with DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, Fmoc-Tyr(3-tBu)-OH was coupled 15 by method 1. After filtering and washing with DMF, the resin was treated with piperidine to remove Fmoc. Subsequently, Fmoc-Phg-OH was coupled by method 3. After filtering and washing with DMF, the resin was treated again with piperidine to remove Fmoc. Subsequently, (R)-3 20 phenylbutyric acid was coupled by method 3. After the end of the reaction, filtering and washing with DMF and DCM were effected, followed by drying of the resin. Cleavage was effected with 3 ml of 95% aqueous TFA. The reaction solution was concentrated under reduced pressure and the 25 residue was dissolved in 1 ml of DMF, followed by HPLC purification. The active fractions were collected, concentrated and freeze-dried to yield 15.6 mg of the titled RA4/ compound. * - 116 - HPLC (method a):RT22.96 FAB-MS:516(M+H*) NMR(method fDMSO-d6): 8 1.16(3H,d,J=7Hz), 1.32(9H,s), 2.41(lH,dd,J=14,8Hz), 2.56(lH,dd,J=14,8Hz), 5 2.74(lH,dd,J=14,9Hz), 2.89(lH,dd,J=14,5Hz), 3.15(lH,ddq,J=8,8,7Hz), 4.38(lH,ddd,J=9,8,5Hz), 5.42(lH,d,J=8Hz), 6.63(lH,d,J=8Hz), 6.81(lH,dd,J=8,2Hz), 7.01(2H,brs), 7.05-7.30(11H,m), 8.30(lH,d,J=8Hz), 8.31(lH,d,J=8Hz), 9.08(1H,s) 10 Example 101 N-((S)-3-phenylbutyryl)-Phg-Tyr(3-tBu)-NH 2 Substituting (S)-3-phenylbutyric acid for the (R)-3 phenylbutyric acid used in Example 100, the procedure of Example 100 was repeated to yield 13.3 mg of the titled 15 compound. HPLC (method a):RT23.00 FAB-MS:516(M+H*) NMR(method fDMSO-d6): 8 1.11(3H,d,J=8Hz), 1.30(9H,s), 2.40(lH,dd,J=14,6Hz), 2.52(lH,dd,J=14,lOHz), 20 2.69(lH,dd,J=14,9Hz), 2.89(lH,dd,J=14,5Hz), 3.13(lH,ddq,J=10,6,8Hz), 4.36(lH,ddd,J=9,8,5Hz), 5.47(1H,d,J=8Hz), 6.62(lH,d,J=8Hz), 6.79(1H,dd,J=8,2Hz), 6.99(lH,d,J=2Hz), 7.00(lH,s), 7.10-7.30(1lH,m), 8.20(lH,d,J=8Hz), 8.43(1H,d,J=8Hz), 9.08(lH,s) 25 Example 102 N-((R)-3-phenylbutyryl)-D-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-D-Phg-OH for the Fmoc-Phg-OH used in Example 100, the procedure of Example 100 was repeated to - 117 yield 7.2 mg of the titled compound. HPLC (method a):RT23.07 FAB-MS:516(M+H*) NMR(method gDMSO-d6): 8 1.13(3H,d,J=7Hz), 1.27(9H,s), 5 2.38-2.64(3H,m), 2.88(1H,dd,J=14,4Hz), 3.15(lH,m), 4.26(lH,m), 5.50(lH,d,J=8Hz), 6.53(lH,d,J=8Hz), 6.69(1H,dd,J=8,1Hz), 6.98(lH,brs), 7.10-7.42(12H,m), 8.48(lH,d,J=8Hz), 8.54(1H,d,J=8Hz), 9.06(1H,s) Example 103 10 N-((S)-3-phenylbutyryl)-D-Phg-Tyr(3-tBu)-NH 2 Substituting Fmoc-D-Phg-OH for the Fmoc-Phg-OH used in Example 101, the procedure of Example 101 was repeated to yield 16.1 mg of the titled compound. HPLC (method a):RT22.98 15 FAB-MS:516(M+H*) NMR(method gDMSO-d6): 8 1.17(3H,dJ=7Hz), 1.27(9H,s), 2.39-2.65(3H,m), 2.91(lH,dd,J=14,3Hz), 3.16(lH,m), 4.28(lH,m), 5.42(1H,d,J=8Hz), 6.55(1H,d,J=8Hz), 6.73(1H,dd,J=8,1Hz), 6.80-7.44(13H,m), 8.37(1H,d,J=8Hz), 20 8.58(1H,d,J=8Hz), 9.07(1H,s) Example 104 L-a-(3-methyl-2-butenyl)glycinoyl-N-Me-Val-Tyr(3-tBu)-NH 2 To a solution in 6 ml of DMF of 228 mg (0.653 mmol) of the N-Me-Val-Tyr(3-tBu)-NH 2 prepared in Example 89, 340 mg 25 (1.40 mmol) of Boc-L-a-(3-methyl-2-butenyl)glycine (Bioorg. Med. Chem. Lett., 2, 387 (1992)) and 189 mg (1.40 mmol) of HOBT, 0.22 ml (1.40 mmol) of DIC was added under cooling with ice. After being stirred at room temperature for a day, - 118 the reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO,, then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated 5 under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 50:1:0.1) to give Boc-L-a-(3-methyl-2-butenyl) glycinoyl-N-Me-Val-Tyr(3-tBu)-NH 2 in 0.17 g (45%). 10 Subsequently, 1 ml of TFA was added to a solution of Boc-L-a-(3-methyl-2-butenyl)glycinoyl-N-Me-Val-Tyr(3-tBu)

NH

2 (0.17 g) in methylene chloride (2 ml) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concetrated under reduced pressure and 15 the resulting residue was diluted with methylene chloride. The solution was washed with saturated aqueous NaHCO 3 . The resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 20:1:0.1) to 20 yield L-a-(3-methyl-2-butenyl)glycinoyl-N-Me-Val-Tyr(3 tBu)-NH 2 in 131 mg (93%). FAB-MS: 475(M+H*) NMR(method gCDCl 3 ): 8 0.79(2H,d,J=6.6Hz), 0.82(lH,d,J=6.6Hz), 0.89(lH,d,J=6.3Hz), 0.95(2H,d,J=6.3Hz), 25 1.36(6H,s), 1.38(3H,s), 1.62(3H,s), 1.69(3H,s), 2.2-2.4(3H,m), 2.67(2H,s), 2.9-3.1(2H,m), 2.97(lH,s), 3.40(6.5/10H,m), 3.65(3.5/10H,m), 4.00(6.5/10H,d,J=10.9Hz), 4.39(3.5/10H,d,J=10.9Hz), 4.50-4.80(lH,m), 4.95-5.10(lH,m), - 119 - 5.57(lH,brs), 5.91(3/10H,brs), 6.07(7/10H,brs), 6.60 6.72(23/10H,m), 6.87-6.96(lH,m), 7.03(7/10H,s), 7.09(3/10H,s), 9.19(7/10H,d,J=7.6Hz) Example 105 5 a-(4-pentynyl)glycinoyl-N-Me-Val-Tyr(3-tBu)-NH 2 (1) Synthesis of Boc-DL-a-(4-pentynyl)glycine To a solution of 0.45 g (4.00 mmol) of potassium t butoxide in 6 ml of THF, 690 mg (3.33 mmol) of N [bis(methyl-thio)methylene]glycine ethyl ester in 2 ml of 10 THF was added at -78 0 C in a nitrogen atmosphere. After stirring for 15 minutes, a solution of 777 mg (4.00 mmol) of 5-iodo-1-pentyne (J. Chem. Soc. 'Perkin Trans. I, 2909 (1990)) in 2 ml of THF was added and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, 15 saturated aqueous NaHCO 3 was added and extraction was effected with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in a mixture of dioxane 20 (2 ml) and water (4 ml) and, after adding 4 ml of a solution of 10% hydrochloric acid in methanol, the reaction mixture was stirred overnight at room temperature. Thereafter, 2 N aqueous NaOH was added to the reaction mixture to make it alkaline and it was extracted with methylene chloride; then, 25 dioxane (5 ml) and di-tert-butyl dicarbonate (1.5 g) were added to the aqueous layer. After being stirred overnight, the aqueous layer was rendered acidic by addition of 2 N hydrochloric acid, extracted with methylene chloride and - 120 dried with anhydrous magnesium sulfate; thereafter, the solvent was distilled off under reduced pressure to give 0.46 g of Boc-DL-a-(4-pentynyl)glycine in crude form. NMR(method gCDCl 3 ): 6 1.45(9H,s), 1.60-1.70(2H,m), 5 1.80(lH,m), 1.97(1H,t,J=2.6Hz), 1.98(lH,m), 2.25(2H,dt,J=2.6,6.9Hz), 4.35(1H,brs),5.02(lH,brs) (2) Synthesis of Boc-a-(4-pentynyl)glycinoyl-N-Me-Val Tyr(3-tbu)-NH 2 To a solution in DMF (5 ml) of 034 g (1.41 mmol) of 10 the crude Boc-DL-a-(4-pentynyl)glycine, 200 mg (0.572 mmol) of N-Me-Val-Tyr(3-tBu)-NH 2 prepared in accordance with Example 89 and 150 mg (1.14 mmol) of HOBT, 0.18 ml (1.14 mmol) of DIC was added under cooling with ice. After being stirred at room temperature for 19 hours, the reaction 15 mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO,, water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting 20 solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 50:1:0.1) to give Boc-a-(4 pentynyl)glycinoyl-N-Me-Val-Tyr(3-tBu) -NH 2 both as a compound of low polarity in an amount of 202 mg (61%) and as a compound of high polarity in an amount of 65 mg (20%). 25 (3) Synthesis of a-(4-pentynyl)glycinoyl-N-Me-Val-Tyr(3 tBu)-NH 2 Each of the above-mentioned compounds of low polarity (195 mg) and high polarity (60 mg) was dissolved in 2 ml of - 121 methylene chloride and, after adding 1 ml of TFA, the mixtures were stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure and the resulting residue was diluted with methylene chloride. The 5 organic layer was washed with saturated aqueous NaHCO 3 . The resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 20:1:0.1) to yield a- (4-pentynyl) -glycinoyl-N-Me-Val-Tyr(3-tBu) -NH 2 from 10 the compound of low polarity in an amount of 101 mg (63%) and from the compound of high polarity in an amount of 17 mg (34%). Compound of low polarity FAB-MS: 473(M+H*) 15 NMR(method gCDCl 3 ): 8 0.75(3H,d,J=6.6Hz), 0.91(3H,d,J=6.3Hz), 1.37(9H,s), 1.4-1.8(4H,m), 1.93(lH,t,J=2.5Hz), 2.17-2.27(3H,m), 2.69(3H,s), 2.82(lH,dd,J=10.1,14.2Hz), 3.18(lH,dd,J=5.6,14.2Hz), 3.53(lH,m), 4.52(lH,d,J=10.9Hz), 4.63(1H, m), 20 5.90(lH,brs), 6.31(lH,brs), 6.64(lH,d,J=7.3Hz), 6.65(1H,d,J=7.9Hz), 6.78(lH,d,J=7.9Hz), 7.06(lH,s) Compound of high polarity FAB-MS: 473(M+H*) NMR(method gCDCl 3 ): 8 0.78-0.97(6H,m), 1.37(6H,s), 25 1.39(3H,s), 1.4-1.8(4H,m), 1.96(lH,m), 2.17-2.22(2H,m), 2.33(lH,m), 2.66(2H,s), 2.87-3.11(2H,m), 2.97(lH,s), 3.43-3.69(14/10H,m), 3.98(7/10H,d,J=10.9Hz), 4.42(3/10H, d,J=10.9Hz), 4.48-4.76(lH,m), 5.43(lH,brs), 5.81(3/10H,brs), - 122 - 6.08(7/10H,brs), 6.62-6.77(2H,m), 6.81(3/1OH,d,J=7.9Hz), 6.90(7/10H,d,J=7.9Hz), 7.03(7/10H,s), 7.10(3/10H,s), 9.03(6/10H,d,J=7.3Hz) Example 106 5 a-(2-butynyl)glycinoyl-N-Me-Val-Tyr(3-tBu)-NH 2 (1) Synthesis of Boc-DL-a-(2-butynyl)glycine ethyl ester To a solution of 0.40 g (3.55 mmol) of potassium t-butoxide in 6 ml of THF, 610 mg (2.96 mmol) of N [bis(methyl-thio)methylene]glycine ethyl ester in 2 ml of 10 THF was added at -78 0 C. After stirring for 20 minutes, a solution of 640 mg (3.55 mmol) of 1-iodo-2-butyne (Chem. Lett., 621 (1981)) in 2 ml of THF was added and the resulting mixture was stirred at room temperature for 30 minutes. Saturated aqueous NaHCO 3 was added to the reaction 15 mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in a mixture of dioxane (2 ml) and water (4 ml) 20 and, after adding 10% hydrochloric acid in methanol (4 ml), the mixture was stirred overnight at room temperature. Thereafter, the reaction mixture was neutralized with 2 N aqueous NaOH, rendered alkaline with saturated aqueous NaHCO 3 , extracted with methylene chloride, dried with 25 anhydrous sodium carbonate and the solvent was distilled off under reduced pressure. To a solution of the resulting residue in 5 ml of methylene chloride, di-tert-butyl bicarbonate (0.65 g) was - 123 added and the, mixture was stirred for 1 hour. The reaction mixture was washed with water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column 5 chromatography (eluting solvent; ethyl acetate:n-hexane = 1:6) to give Boc-DL-a-(2-butynyl)glycine ethyl ester in 575 mg (76%). NMR(method g, CDCl 3 ): b 1.29(3H,t,J=7.3Hz),1.46(9H,s),1.77(3H, t,J=2.6Hz),2.56-2.77(2H,m),4.18-4.27(2H,m),4.38(lH,m),5.30(1 10 H,brs) (2) Synthesis of Boc-a-(2-butynyl)glycinoyl-N-Me-Val-Tyr(3 tBu)

-NH

2 To a solution of 570 mg (2.23 mmol) of Boc-DL-a-(2 butynyl)glycine ethyl ester in a solvent system of methanol 15 (6 ml) and water (2 ml), 140 mg (3.35 mmol) of lithium hydroxide monohydrate was added and the mixture was stirred at room temperature for 2 hours. The mixture was rendered acidic with 2 N hydrochloric acid under cooling with ice, extracted with methylene chloride, dried with anhydrous 20 magnesium sulfate and the solvent was distilled off under reduced pressure to give Boc-DL-a-(2-butynyl)glycine in 0.50 g (quantitative). To a solution in DMF (4 ml) of 123 mg (0.541 mmol) of the Boc-DL-a-(2-butynyl)glycine, 378 mg (1.08 mmol) of N 25 Me-Val-Tyr(3-tBu)-NH 2 prepared in accordance with Example 89 and 146 mg (1.08 mmol) of HOBT, 0.13 ml (0.811 mmol) of DIC was added under cooling with ice. After being stirred overnight at room temperature, the reaction mixture was - 124 diluted with ethyl acetate and washed with saturated aqueous NaHCO 3 , water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected 5 to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 50:1:0.1) to give Boc-a-(2-butynyl)glycinoyl-N-Me Val-Tyr(3-tBu)-NH 2 both as a compound of low polarity in an amount of 138 mg and as a compound of high polarity in an 10 amount of 59 mg. (3) Synthesis of a-(2-butynyl)glycinoyl-N-Me-Val-Tyr(3 tBu)

-NH

2 Each of the above-mentioned compounds of low polarity (138 mg) and high polarity (59 mg) was dissolved in 2 ml of 15 methylene chloride and, after adding 1 ml of TFA, the mixtures were stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure and the resulting residue was diluted with methylene chloride, followed by washing with saturated aqueous NaHC 3 . The 20 resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 20:1:0.1) to yield a-(2-butynyl)glycinoyl-N-Me-Val-Tyr(3-tBu) -NH 2 from the compound of low polarity in an amount of 80 mg and from 25 the compound of high polarity in an amount of 47 mg. Compound of low polarity FAB-MS: 459(M+H*) NMR(method gCDCl 3 ): 8 0.75(3H,d,J=6.6Hz), - 125 - 0.90(3H,d,J=6.6Hz), 1.38(9H,s), 1.77(3H,s), 2.1-2.5(6H,m), 2.74(3H,s), 2.81(1H,dd,J=9.9,14.2Hz), 3.18(lH,dd,J=5.6,14.2Hz), 3.66(lH,dd,J=5.0,7.6Hz), 4.47(lH,d,J=11.2Hz), 4.57(lH, m), 5.66(lH,brs), 6.26(lH,brs), 5 6.47(1H,d,J=7.3Hz), 6.64(1H,d,J=7.9Hz), 6.78(lH,d,J=7.9Hz), 7.05(1H,s) Compound of high polarity FAB-MS: 459(M+H*) NMR(method g.CDCl 3 ): 8 0.78-0.96(6H,m), 1.38(6H,s), 10 1.39(3H,s), 1.78(3H,s), 2.30-2.45(4H,m), 2.68(2H,s), 2.92-3.13(2H,m), 2.97(1H,s), 3.48(1H,dd,J=4.3,9.2Hz), 3.98(7/1OH,d,J=11.2Hz), 4.42(3/10H, d,J=11.2Hz), 4.53 4.78(lH,m), 5.52(lH,brs), 6.14(lH,brs), 6.62-6.70(2H,m), 6.81(3/10H,d,J=7.9Hz), 6.90(7/10H,d,J=7.9Hz), 7.04(7/10H,s), 15 7.10(3/10H,s), 9.10(1H,d,J=7.3Hz) Example 107 N-( (S)-3-phenylbutyryl)-N-Me-Val-Tyr(3-tBu)-NH 2 To a solution in DMF (3 ml) of 0.11 ml (0.736 mmol) of (S)-3-phenyl-n-butyric acid, 234 mg (0.670 mmol) of N-Me 20 Val-Tyr(3-tBu)-NH 2 prepared in accordance with Example 89, and 99 mg (0.736 mmol) of HOBT, 0.11 ml (0.736 mmol) of DIC was added under cooling with ice. After being stirred at room temperature for 25 hours, the reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO 3 , 25 water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel C3RA4/ column chromatography (eluting solvent consisting of -126 chloroform, methanol and aqueous ammonia at a ratio of 50:1:0.1) to yield N-((S)-3-phenylbutyryl)-N-Me-Val-Tyr(3 tBu)-NH 2 in 259 mg (78%). EI-MS: 496(M *) 5 NMR(method gCDCl 3 ): 8 0.76(3H,d,J=6.6Hz), 0.89(3H,d,J=6.3Hz), 1.27(3H,d,J=6.9Hz), 1.34(9H,s), 2.17-2.31(lH,m), 2.38-2.57(2H,m), 2.72(3H,s), 2.81(lH,dd,J=8.2,14.2Hz), 2.96(1H,dd,J=6.3,14.2Hz), 3.34(lH,m), 4.46(1H,d,J=11.2Hz), 4.56(1H, m), 5.50(1H,s), 10 5.59(lH,brs), 6.00(lH,brs), 6.45(1H,d,J=7.9Hz), 6.66(lH,d,J=7.6Hz), 6.78(1H,dd,J=1.7,7.9Hz), 7.05(1H,d,J=1.7Hz), 7.20-7.36(5H,m) Example 108 N-((R)-3-phenylbutyryl)-N-Me-Val-Tyr(3-tBu)-NH 2 15 To a solution in DMF (3 ml) of 0.085 ml (0.558 mmol) of (R)-3-phenyl-n-butyric acid, 150 mg (0.429 mmol) of N-Me Val-Tyr(3-tBu)-NH 2 prepared in accordance with Example 89, and 75 mg (0.558 mmol) of HOBT, 0.087 ml (0.558 mmol) of DIC was added under cooling with ice. After being stirred at 20 room temperature for 25 hours, the reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO 3 , water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel 25 column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 50:1:0.1) to yield N-((R)-3-phenylbutyryl)-N-Me-Val-Tyr(3 tBu)-NH 2 in 186 mg (87%). - 127 - EI-MS: 497(M*+1) NMR(method gCDCl 3 ): 8 0.51(3H,d,J=6.6Hz), 0.82(3H,d,J=6.6Hz), 1.31(3H,d,J=7.3Hz),1.38(9H,s), 2.04-2.23(lH,m), 2.38(lH,dd,J=7.3,14.8Hz), 5 2.65(1H,dd,J=7.6,14.8Hz), 2.73(3H,s), 2.90(lH,dd,J=7.9,14.2Hz), 3.00(1H,dd,J=6.3,14.2Hz), 3.30(lH,m), 4.36(1H,d,J=10.9Hz), 4.60(1H, m), 5.67(lH,brs), 5.99(lH,brs), 6.15(lH,brs), 6.63(1H,d,J=8.3Hz), 6.76(1H,d,J=7.9Hz), 10 6.82(1H,d,J=7.9Hz), 7.07(lH,s), 7.17-7.29(5H,m) Example 109 N-($-aminohydrocinnamoyl)-N-Me-Val-Tyr(3-tBu)-NH 2 To a mixture of 0.67 g (4.05 mmol) of $-aminohydro cinnamic acid, 0.45 g (4.26 mmol) of sodium carbonate, 2.5 15 ml of 2 N aqueous NaOH, 8 ml of water and 8 ml of dioxane, 0.93 g (4.26 mmol) of di-tert-butyl dicarbonate was added and the resulting mixture was stirred at room temperature for 3 hours. Under cooling with ice, the reaction mixture was rendered acidic with conc. hydrochloric acid, extracted 20 with methylene chloride, dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 1.14 g of N-Boc-p-aminohydrocinnamic acid. To a solution in DMF (5 ml) of 0.27 g (1.03 mmol) of N-Boc-$-aminohydrocinnamic acid, 0.24 g (0.687 mmol) of N 25 Me-Val-Tyr(3-tBu)-NH 2 prepared in accordance with Example 89 and 0.23 g (1.72 mmol) of HOBT, 0.27 ml (1.72 mmol) of DIC was added under cooling with ice. After being stirred at room temperature for a day, the reaction mixture was diluted - 128 with ethyl acetate and washed with saturated aqueous NaHCO 3 , water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel 5 column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 60:1:0.1) to give N-(N-boc- -aminohydro-cinnamoyl)-N-Me-Val Tyr(3-tBu)-NH 2 in 291 mg (71%). A portion (285 mg) of the N-(N-Boc-$-aminohydro 10 cinnamoyl)-N-Me-Val-Tyr(3-tBu)-NH 2 was dissolved in 2 ml of methylene chloride and, after adding 1 ml of TFA, the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure and the resulting residue was diluted with methylene chloride and 15 washed with saturated aqueous NaHCO 3 . The resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 20:1:0.1) to yield N-($-aminohydro cinnamoyl)-N-Me-Val-Tyr(3-tBu)-NH 2 in 197 mg (83%). 20 FAB-MS: 497(M+H*) Example 110 N-(2-amino-3-phenylpropyl)-Phg-Tyr(3-tBu)-NH 2 To a solution of 120 mg (0.325 mmol) of Phg-Tyr(3 tBu)-NH 2 and 112 mg (0.396 mmol) of Z-phenylalaninal (J. Org. 25 Chem., 5.1, 28 (1992)) in 3 ml of MeCN, 0.1 ml of acetic acid and 41.5 mg (0.661 mmol) of sodium cyanoborohydride were added under cooling with ice and the resulting mixture was stirred for 2 hours. After adding water, the reaction - 129 mixture was extracted with ethyl acetate and washed with water and saturated brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column 5 chromatography (eluting solvent; chloroform:methanol = 20:1) to give N-(2-benzoxycarbonylamino-3-phenylpropyl)-Phg-Tyr(3 tBu)-NH 2 in 187 mg (89%). To a solution of 40.0 mg (0.0664 mmol) of N-(2 benzoxycarbonylamino-3 -phenylpropyl) -Phg-Tyr( 3-tBu) -NH 2 in 10 methanol (1 ml), 10% palladium carbon (15.0 mg) was added and the mixture was stirred overnight in a hydrogen atmosphere at room temperature. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column 15 chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 10:1:0.1) to yield N-(2-amino-3-phenylpropyl)-Phg-Tyr(3-tBu)-NH 2 in 29.0 mg (92%). EI-MS: 503(M*+1) 20 NMR(method gCDCl 3 ): 8 1.36(9H,s), 2.20-3.05(7H,m), 3.47(lH,s)4.08(1H,d, J=4.6Hz), 4.54-4.72(lH,m), 5.56(lH,brs), 6.56(lH,d,J=7.9Hz), 6.81(lH,d,J=7.9Hz), 7.02-7.30(11H,m), 8.01(lH,d,J=8.4Hz) Example 111 25 N-(2-amino-3-phenylpropyl)-N-Me-Phg-Tyr(3-tBu)-NH 2 To a solution of 60.0 mg (0.0943 mmol) of N-(2 benzoxycarbonylamino-3-phenylpropyl)-Phg-Tyr(3-tBu)-NH 2 in MeCN (1 ml), 0.081 ml (0.94 mmol) of 35% aqueous - 130 LQJ formaldehyde, 0.1 ml of acetic acid and 18.7 mg (0.283 mmol) of sodium cyanoborohydride were added under cooling with ice and the resulting mixture was stirred for 2 hours. The reaction mixture was diluted with water, extracted with 5 chloroform and washed with saturated brine. The organic layer was dried with magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in methanol (1 ml) and, after adding palladium carbon (15.0 mg), the solution was stirred at room 10 temperature for 3 days in a hydrogen atmosphere. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 15 10:1:0.1) to yield N-(2-amino-3-phenyl-propyl)-N-Me-Phg Tyr(3-tBu)-NH 2 in 29.7 mg (61%). FAB-MS: 517(M+H*) NMR(method g, CDCl 3 ): 6 1.38(9H,s), 2.07(2H,s), 2.16-3.20(7H,m), 3.47(3H,s), 4.13(1H,s), 4.60-4.80(lH,m), 20 5.46-5.60(lH,m), 6.52-7.32(13H,m), 8.15(lH,d,J=7.9Hz) Example 112 N-(phenylpyruvinoyl)-N-Me-Val-Tyr(3-tBu)-NH 2 To a solution of 179 mg (1.09 mmol) of phenylpyruvic acid in methylene chloride (2 ml), 0.079 ml (1.1 mmol) of 25 thionyl chloride was added and the resulting mixture was stirred at 60 0 C for 1 hour. The reaction mixture was distilled off under reduced pressure and the resulting RA) residue was dissolved in methylene chloride (2 ml); to the - 131 solution, 190 mg (0.544 mmol) of N-Me-Val-Tyr(3-tBu)-NH 2 and 0.152 ml (1.09 mmol) of triethylamine were added under cooling with ice. After stirring at room temperature for 2 hours, water was added to the reaction mixture, which was 5 then extracted with chloroform and washed with saturated brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of methylene chloride, methanol 10 and aqueous ammonia at a ratio of 20:1:0.1) to yield N (phenylpyruvinoyl)-N-Me-Val-Tyr(3-tBu)-NH 2 in 50.7 mg (19%). NMR(method gCDCl 3 ): 8 0.97(3H,d,J=6.6Hz), 0.99(3H,d,J=6.6Hz), 1.37(9H,s), 2.30-2.52(lH,m), 2.85(3H,s), 2.92-3.16(2H,m), 4.53(1H,d,J=10.9Hz), 15 4.63(1H,dd,J=7.3,7.3Hz), 5.46(2H,brs), 5.84(lH,brs), 6.59(1H,d,J=7.9Hz), 6.95(1H,d,J=6.9Hz), 7.12(1H,s), 7.44(2H,t,J=7.6Hz), 7.60-7.70(lH,m), 7.95(2H, d,J=7.6Hz) Example 113 N-phenyl-Gly-N-Me-Val-Tyr(3-tBu)-NH 2 20 To a solution of 108 mg (0.430 mmol) of Boc-N-phenyl Gly in THF (1 ml), 0.048 ml (0.44 mmol) of N methylmorpholine, 0.056 ml (0.43 mmol) of isobutyl chloroformate, a solution of 100 mg (0.287 mmol) of N-Me Val-Tyr(3-tBu)-NH 2 in DMF (1 ml), and 0.060 ml (0.43 mmol) 25 of triethylamine were added at -15 0 C and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed successively with saturated NaHCO 3 , water and saturated - 132 brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 1:1) to give Boc 5 N-phenyl-Gly-N-Me-Val-Tyr(3-tBu)-NH 2 in 139 mg (83%). To a solution of 130 mg (0.223 mmol) of Boc-N-phenyl Gly-N-Me-Val-Tyr(3-tBu)-NH 2 in methylene chloride (1 ml), TFA (1 ml) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was 10 concentrated under reduced pressure and the resulting residue was dissolved in methylene chloride, followed by successive washing with saturated aqueous NaHCO 3 and saturated brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the 15 resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 10:1:0.1) to yield N-phenyl-Gly-N-Me-Val-Tyr(3-tBu)-NH 2 in 69.7 mg (65%). FAB-MS: 483(M+H*) 20 NMR(method gCDCl 3 ): 8 0.78(3H,d,J=6.6Hz), 0.94(3H,d,J=6.3Hz), 1.35(9H,s), 2.16-2.36(lH,m), 2.66(3H,s), 2.78(lH,dd,J=10.2,14.2Hz), 3.13(lH,dd,J=5.5,14.2Hz), 3.42(1H,d,J=16.5Hz), 3.74(lH,d,J=16.5Hz), 4.48-4.64(2H,m), 4.86(lH,brs), 5.39(lH,brs), 6.07(lH,brs), 6.27(lH,d,J=8.3Hz), 25 6.34(lH,d,J=7.2Hz), 6.67(2H,d,J=8.3Hz), 6.74-6.84(lH,m), 7.05(lH,s), 7.24-7.30(lH,m) Example 114 N-Me-N-phenyl-Gly-N-Me-Val-Tyr(3-tBu)-NH 2 - 133 - To a solution of 184 mg (0.646 mmol) of Z-N-phenyl-Gly in THF (2 ml), 0.071 mg (0.65 mmol) of NMM, 0.084 ml (0.65 mmol) of isobutyl chloroformate, a solution of 150 mg (0.430 mmol) of N-Me-Val-Tyr(3-tBu)-NH 2 in DMF (2 ml) and 0.090 ml 5 (0.65 mmol) of triethylamine were added under cooling with ice and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous NaHCO 3 , water and saturated brine. The organic 10 layer was dried with magnesium sulfate and the solvent was distilled off under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 2:1) to give Z-N-(phenyl) Gly-N-Me-Val-Tyr(3-tBu)-NH 2 in 186 mg (70%). 15 To a solution of 180 mg (0.292 mmol) of Z-N-phenyl Gly-N-Me-Val-Tyr(3-tBu)-NH 2 in methanol (2 ml), 10% palladium carbon (100 mg) was added and the mixture was stirred overnight in a hydrogen atmosphere at room temperature. To the reaction mixture, 0.50 ml (5.83 mmol) 20 of 35% formaldehyde was added and the mixture was stirred for additional 3 hours in a hydrogen atmosphere at room temperature. After filtering, water was added to the filtrate and the mixture was extracted with chloroform and washed with saturated brine. The organic layer was dried 25 with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n RA4 hexane = 2:1) to yield N-Me-N-phenyl-Gly-N-Me-Val-Tyr(3 -134 tBu)-NH 2 in 32.0 mg (22%). FAB-MS: 497(M+H*) NMR(method gCDCl 3 ): 5 0.78(3H,d,J=6.9Hz), 0.88(3H,d,J=6.3Hz), 1.37(9H,s), 2.18-2.36(lH,m), 5 2.63(1H,d,J=4.6Hz), 2.84(3H,s), 2.88-2.96(lH,m), 2.99(3H,s), 3.92(1H,d,J=16.5Hz), 4.06(1H,d,J=16.5Hz), 4.12(1H,d,J=7.3Hz), 4.62(1H,dd,J=6.6,7.9Hz), 5.35(2H,brs), 5.92(lH,brs), 6.56(lH,d,J=7.9Hz), 6.64(2H,d,J=7.9Hz), 6.74(lH,t,J=7.9Hz), 6.82(1H,d,7.9Hz), 7.08(1H,s), 7.21(2H,t,J=7.9Hz), 10 7.35(lH,d,J=4.OHz) Example 115 N-(3-phenylbutyl)-Val-Tyr(3-tBu)-NH 2 To a solution of 330 mg (0.985 mmol) of Val-Tyr(3 tBu)-NH 2 and 146 mg (0.986 mmol) of phenylbutylaldehyde in 15 MeCN (2 ml), 0.1 ml of acetic acid and 124 mg (1.97 mmol) of sodium cyanoborohydride were added under cooling with ice and the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate and washed with saturated 20 brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol = 10:1) to yield N-(3 phenylbutyl)-Val-Tyr(3-tBu)-NH 2 in 236 mg (51%). 25 FAB-MS:468(M+H*) NMR(method gCDCl 3 ): 8 0.57(4/3H,d,J=6.9Hz), 0.62(5/3H,d,J=6.9Hz), 0.75(4/3H,d,J=6.6Hz), 0.62(5/3H,d,J=6.6Hz), 1.23(3H,d,J=6.9Hz), 1.38(9H,s), - 135 - 1.56-1.76(2H,m), 1.86-2.02(lH,m), 2.20-2.32(lH,m), 2.36(4/9H,d,J=6.9Hz), 2.39(5/9H,d,J=6.9Hz), 2.64-2.74(lH,m), 2.76(lH,d,J=4.3Hz), 2.94-3.08(2H,m), 4.50-4.64(lH,m), 5.10-5.28(lH,m), 5.88(5/9H,brs), 6.00(4/9H,brs), 5 6.59(lH,d,J=7.9Hz), 6.93(1H,d,J=7.9Hz), 7.06(1H,s), 7.10-7.36(5H,m), 7.64-7.76(lH,m) Example 116 N- (2-amino-3-phenylpropyl) -Val-Tyr( 3-tBu) -NH 2 To a solution of 106 mg (0.316 mmol) of Val-Tyr(3 10 tBu)-NH 2 and 90.0 mg (0.318 mmol) of Z-phenylalaninal in THF (2 ml), 300 mg of magnesium sulfate and 40.0 mg (0.637 mmol) of sodium cyanoborohydride were added under cooling with ice and the resulting mixture was stirred at room temperature for 2 hours. After filtering, water was added to the 15 filtrate, which was extracted with chloroform and washed with saturated brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol = 20:1) 20 to give N-[2-benzoxycarbonylamino)-3-phenylpropyl]-Val Tyr(3-tBu)-NH 2 in 95.7 mg (50%). To a solution of 94.1 mg (0.156 mmol) of N-[2 (benzoxycarbonylamino)-3-phenylpropyl]-Val-Tyr(3-tBu)-NH 2 in methanol (2 ml), palladium carbon (50.0 mg) was added and 25 the mixture was stirred overnight in a hydrogen atmosphere at room temperature. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography -136- (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 10:1:0.1) to yield N-(2-amino 3-phenylpropyl)-Val-Tyr(3-tBu)-NH 2 in 47.0 mg (64%). FAB-MS:469(M+H*) 5 NMR(method gCDCl 3 ): 6 0.75(3H,d,J=6.9Hz), 0.87(3H,d,J=6.9Hz), 1.38(9H,s), 1.90-2.08(lH,m), 2.38 2.54(3H,m), 2.66-2.78(lH,m), 2.81(1H,d,J=4.6Hz), 2.92 3.08(2H,m), 4.60-4.72(lH,m), 5.20-5.36(lH,m), 6.55(lH,brs), 6.61(lH,d,J=7.9Hz), 6.92(1H,d,J=7.9Hz), 7.07(1H,s), 10 7.13(2H,d,J=6.9Hz), 7.16-7.36(3H,m), 7.74(1H,d,J=8.2Hz) Example 117 2-[(2-amino-3-phenylpropyl)amino]-N-[2-amino-1-[(3-tert butyl-4-hydroxyphenyl)methyl]ethyl]-3-methyl butanamide (1) Synthesis of N-[2-(benzoxycarbonylamino)-1-[(3-tert 15 butyl-4-hydroxyphenyl)methyl]ethyl]-2-(tert butoxycarbonylamino)-3-methyl butanamide To a solution of 2.00 g (7.97 mmol) of Tyr(3-tBu)-OMe in a mixture of 1,4-dioxane (15 ml) and water (15 ml), 929 mg (8.76 mmol) of sodium carbonate and 1.91 g (8.75 mmol) of 20 di-tert-butyl dicarbonate were added under cooling with ice and the resulting mixture was stirred for 2 hours. Under cooling with ice, saturated aqueous NH 4 Cl was added and the mixture was extracted with chloroform and washed with saturated brine. The organic layer was dried with magnesium 25 sulfate and the solvent was distilled off under reduced pressure; the resulting residue was dissolved in a mixture of ethanol (20 ml) and THF (20 ml); under cooling with ice, 520 mg (23.9 mmol) of lithium borohydride was added to the -137 solution and the mixture was stirred for 4 hours. To the reaction mixture, 2 N aqueous HCl was added, followed by extraction with chloroform and washing with water and saturated brine. The organic layer was dried with magnesium 5 sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 1:1) to give [1-[(3-tert-butyl-4-hydroxyphenyl)methyl]-2 hydroxyethyl]carbamic acid tert-butyl ester in 2.26 g (88%). 10 To a solution of 2.26 g (7.00 mmol) of the [1-[(3 tert-butyl-4-hydroxyphenyl)methyl)-2-hydroxyethyl]carbamic acid tert-butyl ester in THF (25 ml), 3.67 g (14.0 mmol) of triphenylphosphine, 2.06 g (14.0 mmol) of phthalimide and 2.76 ml (14.0 mmol) of diiosopropyl azodicarboxylate were 15 added under cooling with ice and the resulting mixture was stirred for 1 hour. After adding water, the reaction mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the result 20 ing residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 1:2) to give a mixture containing [1-[(3-tert-butyl-4 hydroxyphenyl)methyll-2-(1,3-dioxo-1,3-dihydroisoindol-2 yl)ethyllcarbamic acid tert-butyl ester. 25 To a solution in methanol (15 ml) of the mixture containing [1-[(3-tert-butyl-4-hydroxyphenyl)methyl)-2-(1,3 dioxo-1,3-dihydroisoindol-2-yl)ethyl]carbamic acid tert butyl ester, hydrazine monohydrate (2 ml) was added and the -138 U*

CL)

resulting mixture was stirred at room temperature for 4 hours. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting 5 of chloroform, methanol and aqueous ammonia at a ratio of 10:1:0.1) to give [2-amino-1-[(3-tert-butyl-4 hydroxyphenyl)methyl]ethyl]carbamic acid tert-butyl ester in 1.55 g (69%). To a solution of 1.53 g (4.75 mmol) of [2-amino-1-[(3 10 tert-butyl-4-hydroxyphenyl)methyl]ethyl]carbamic acid tert butyl ester in methylene chloride (20 ml), 0.725 ml (5.23 mmol) of triethylamine and 0.746 ml (5.23 mmol) of benzyl chloroformate were added and the resulting mixture was stirred for 15 minutes. Under cooling with ice, saturated 15 aqueous NaHCO 3 was added and the mixture was extracted with methylene chloride and washed with saturated brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting 20 solvent; ethyl acetate:n-hexane = 1:1) to give [2 (benzoxycarbonylamino)-1-[(3-tert-butyl-4-hydroxyphenyl) methyllethylicarbamic acid tert-butyl ester in 1.78 g (82%). NMR(method gCDCl 3 ): 8 1.39(9H,s), 1.40(9H,s), 2.60 2.80(2H,m), 3.08-3.38(2H,m), 3.80-3.94(lH,m), 4.58 25 4.72(lH,m), 5.10(2H,s), 5.28(lH,brs), 6.59(1H,d,J=7.9Hz), 6.85(1H,d,J=7.9Hz), 7.02(1H,s), 7.34(5H,brs) To a solution of 402 mg (0.882 mmol) of [2-(benzoxy carbonylamino)-1-[(3-tert-butyl-4-hydroxyphenyl)-methyl] -139 ethylicarbamic acid tert-butyl ester in methylene chloride (2 ml), TFA (2 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was distilled off under reduced pressure and the resulting 5 residue was dissolved in DMF (3 ml); to the solution, 287 mg (1.32 mmol) of Boc-Val, 179 mg (1.32 mmol) of HOBT, 162 mg (1.33 mmol) of DMAP and 254 mg (1.32 mmol) of WSCI-HCl were added and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted 10 with ethyl acetate and washed successively with saturated aqueous NaHCO,, water and saturated brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl 15 acetate:n-hexane = 1:1) to give N-[2-(benzoxycarbonylamino) 1-[(3-tert-butyl-4-hydroxyphenyl)-methyllethyl]-2-(tert butoxycarbonylamino)-3-methyl butanamide in 363 mg (74%). (2) Synthesis of 2-[(2-amino-3-phenylpropyl)amino]-N-[ 2 amino-l-[(3-tert-butyl-4-hydroxyphenyl)methyl]ethyl]-3 20 methyl butanamide To a solution of 436 mg (0.786 mmol) of N-[2-(benzoxy carbonylamino)-1-[(3-tert-butyl-4 hydroxyphenyl)methyl]ethyl]-2-(tert-butoxycarbonylamino)-3 methyl butanamide in methylene chloride (2 ml), TFA (2 ml) 25 was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and to the residue, saturated aqueous NaHCO 3 was added under cooling with ice and the mixture was - 140 extracted with chloroform and washed with saturated brine. The organic layer was dried with magnesium sulfate and the solvent was distilled off under reduced pressure; the resulting residue was dissolved in MeCN (3 ml) and under 5 cooling with ice, 245 mg (0.866 mmol) of Z-phenylalaninal, 0.1 ml of acetic acid and 98.8 mg (1.57 mmol) of sodium cyanoborohydride were added to the solution, which was then stirred for 3 hours. After adding water, the solution was extracted with chloroform and washed with saturated brine. 10 The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 1:1) to give N-[2 benzoxycarbonylamino-1-[(3-tert-butyl-4-hydroxyphenyl) 15 methyl]ethyl]-2-[[2-(benzoxycarbonylamino)-3-phenylpropyl] amino]-3-methyl butanamide in 282 mg (50%). To a solution of 132 mg (0.183 mmol) of N-[2-benzoxy carbonylamino-1-[(3-tert-butyl-4-hydroxyphenyl) methyl]ethyl]-2-[[2-(benzoxycarbonylamino)-3-phenylpropyl] 20 amino]-3-methyl butanamide in methanol (2 ml), 10% palladium carbon (80 mg) was added and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 days. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica 25 gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 10:1:0.1) to yield 2-[(2-amino-3-phenyl-propyl)amino]-N-[2 ~RA amino-l-[(3-tert-butyl-4-hydroxyphenyl)-methyllethyl]-3 -141methyl butanamide in 24.2 mg (29%). FAB-MS:455(M+H*) NMR(method gCDCl 3 ): 8 0.70(3H,dd,J=2.0,6.6Hz), 0.84(3H,d,J=6.9Hz), 1.37(9H,s), 1.98-2.04(lH,m), 2.24 5 2.86(9H,m), 2.94-3.12(lH,m), 4.10-4.26(lH,m), 6.62(lH,d,J=7.9Hz), 6.87(lH,d,J=7.9Hz), 7.00(1H,s), 7.12 7.34(5H,m) Example 118 N-[2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-3-methyl 10 2-(N-methyl-N-phenylalaninoylamino)butanamide (1) Synthesis of Z-N,O-dibenzyl-Tyr(3-tBu)-OMe To a solution of 3.0 g (7.78 mmol) of Z-Tyr(3-tBu)-OMe in DMF (20 ml), 0.68 g (17.1 mmol) of sodium hydride was added under cooling with ice and the mixture was stirred for 15 15 minutes; thereafter, 2.3 ml (19.5 mmol) of benzyl bromide was added. After stirring for additional 3 hours, saturated aqueous NaHCO 3 was added to the reaction mixture, which was extracted with ethyl acetate and washed with water and saturated brine. The organic layer was dried with anhydrous 20 magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 1:5) to give Z-N,O-dibenzyl-Tyr(3-tBu)-OMe in 4.14 g (94%). (2) Synthesis of N-benzyl-2-(4-benzyloxy-3-tert 25 butylphenyl)-1-methyl-N-(benzyloxycarbonyl)ethylamine To a solution of 4.14 g (7.32 mmol) of Z-N,O-dibenzyl Tyr(3-tBu)-OMe in a mixture of ethanol (36 ml) and THF (6 ml), 11.0 ml (22.0 mmol) of a solution of 2 M lithium - 142 borohydride in THF was added under cooling with ice and the resulting mixture was stirred overnight at room temperature. After adding water, the reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried with 5 anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in methylene chloride (50 ml) and under cooling with ice, 2.0 ml (14.4 ml) of triethylamine and 0.72 ml (9.36 mmol) of methanesulfonyl chloride were added in 10 succession and the resulting mixture was stirred for 30 minutes. The reaction mixture was washed with saturated aqueous NaHCO 3 and the organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure; there-after, the resulting 15 residue was dissolved in THF (10 ml) and 28.0 ml (28.0 mmol) of a solution of 1 M lithium triethylborohydride in THF was added. After stirring the mixture for 3 hours, water was added under cooling with ice and extraction was effected with methylene chloride. The organic layer was dried with 20 anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n hexane = 1:5) to give N-benzyl-2-(4-benzyloxy-3-tert butylphenyl)-1-methyl-N-(benzyloxycarbonyl)ethylamine in 25 2.35 g (61%). (3) Synthesis of 2-(3-tert-butyl-4-hydroxyphenyl)-1 methylethylamine A suspension ,of 2.35 g (4.50 mmol) of N-benzyl-2-(4 -143 A. Abenzyloxy-3-tert-butylphenyl)-1-methyl-N (benzyloxycarbonyl)-ethylamine and 0.50 g of a 20% palladium hydride on carbon catalyst in methanol (30 ml) was stirred overnight in a hydrogen atmosphere. After filtering off the 5 catalyst, the solvent was distilled off under reduced pressure to give 2-(3-tert-butyl-4-hydroxyphenyl)-1 methylethyl-amine in 0.90 g (96%). NMR(method gCDCl 3 ): 8 1.16(3H,d,J=6.6Hz), 1.39(9H,s), 2.45(lH,dd,J=4.9, 13.3Hz), 2.69(1H,dd,J=4.9,13.3Hz), 10 3.15(lH,m), 3.5(2H,brs), 6.58(1H,d,J=7.9Hz), 6.83(lH,dd,J=1.6,7.9Hz), 7.03(lH,d,J=1.6Hz) (4) Synthesis of N-[2-(3-tert-butyl-4-hydroxyphenyl)-1 methylethyl]-3-methyl-2-(methylamino)butanamide To a solution of 0.31 g (1.50 mmol) of 2-(3-tert 15 butyl-4-hydroxyphenyl)-1-methylethylamine, 0.40 g (1.50 mmol) of Z-N-Me-Val-OH and 0.30 g (2.25 mmol) of HOBT in DMF (5 ml), 0.35 ml (2.25 mmol) of DIC was added under cooling with ice. After being stirred at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate 20 and washed successively with saturated aqueous NaHCO 3 , water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol 25 = 125:1) to give 2-[N-(benzyloxycarbonyl)-N-methylamino] -N [2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-3 methylbutanamide in 0.55 g (81%). A suspension of 0.54 g (1.19 mmol) of 2-[N-(benzyloxy - 144 carbonyl)-N-methylamino]-N-[2-(3-tert-butyl-4 hydroxyphenyl)-1-methylethyl]-3-methylbutanamide and 0.10 g of a 20% palladium hydroxide on carbon catalyst in methanol (8 ml) was stirred in a hydrogen atmosphere for 2 hours. 5 After filtering off the catalyst, the solvent was distilled off under reduced pressure to give N-[2-(3-tert-butyl-4 hydroxyphenyl) -1-methylethyl] - 3-methyl- 2- (methyl amino)butanamide in 0.36 g (95%). (5) N-[2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-3 10 methyl-2-(N-methyl-N-phenylalaninoylamino)butanamide To a solution of 0.36 g (1.12 mmol) of N-[2-(3-tert butyl-4-hydroxyphenyl) -1-methylethyl] -3-methyl-2- (methyl amino)butanamide, 0.75 g (2.81 mmol) of Boc-Phe-OH and 0.38 g (2.81 mmol) of HOBT in DMF (5 ml), 0.44 ml (2.81 mmol) of 15 DIC was added under cooling with ice. After being stirred at room temperature for 2.5 days, the reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous NaHCO,, water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate and 20 concentrated under reduced pressure; the resulting residue was subjected to silica gel colunn chromatography (eluting solvent; chloroform:methanol = 80:1) to give N-[2-(3-tert butyl-4-hydroxyphenyl) -1-methylethyl] -2- [N- (N-Boc-phenyl alaninoyl)-N-methylaminol-3-methylbutanamide in 333 mg (52%). 25 The N-[2-(3-tert-butyl-4-hydroxyphenyl)-1 methylethyll -2- [N- (N-Boc-phenylalaninoyl) -N-methylamino] -3 methylbutanamide (333 mg) was dissolved in methylene chloride (4 ml) and, after adding TFA (2 ml), the solution - 145 was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure and the resulting residue was diluted with methylene chloride and washed with saturated aqueous NaHCO 3 . The resulting residue was 5 subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 75:1:0.1) to yield N-[2-(3-tert-butyl 4-hydroxyphenyl)-1-methylethyl]-3-methyl-2-(N-methyl-N phenylalaninoylamino)butanamide in 164 mg (60%). 10 EI-MS: 468(M +I1) NMR(method gCDCl 3 ): 8 0.72(3/2H,d,J=6.6Hz), 0.81(3/2H,d,J=6.6Hz), 0.93(3/2H,d,J=6.6Hz), 0.94(3/2H,d,J=6.3Hz), 1.07(3/2H,d,J=6.6Hz), 1.08(3/2H,d,J=6.6Hz), 1.37(4H,s), 1.40(5H,s), 2.23 15 2.42(lH,m), 2.43-2.90(3H,m), 2.75(5/3H,s), 2.84(4/3H,s), 3.19(1/2H,dd,J=4.3,13.8Hz), 3.62(1/2H,m), 3.82-3.88(lH,m), 4.23(lH,m), 4.47(2/5H, d,J=10.9Hz), 6.00(3/5H,d,J=8.2Hz), 6.61(2/5H,d,J=7.9Hz), 6.66(3/5H,dd,J=2.0,7.9Hz), 6.77(3/5H,d,J=7.9Hz), 6.83(2/5H,dd,J=2.0,7.9Hz), 20 6.99(3/5H,d,J=2.OHz), 7.05(2/5H,d,J=2.OHz), 7.1-7.4(7H,m), 8.22(3/5H,d,J=8.3Hz) Example 119 Phe-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 (1) Synthesis of Z-N-Me-Val-N-Me-Tyr(3-tBu)-OMe 25 To a solution of 3.25 g of Z-N-Me-Val-OH, 2.2 g of N-Me-Tyr(3-tBu')-OMe and 1.88 g of HOBT in DMF (30 ml), DIC (1.9 ml) was added under cooling with ice and the mixture was stirred at room temperature for 23 hours. Water was - 146 added to the reaction mixture and extraction was effected with ether. The extract was washed with saturated brine and the organic layer was dried with sodium sulfate. After distilling off the solvent under reduced pressure, the 5 resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 100:10:1) to give Z-N-Me-Val-N-Me-Tyr(3-tBu)-OMe in 1.96 g (47%). (2) Synthesis of Z-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 10 To a solution of 1.96 g of Z-N-Me-Val-N-Me-Tyr(3-tBu) OMe in 1,4-dioxane (40 ml), 2 N NaOH (5 ml) was added at room temperature and the mixture was stirred for 2 hours. The reaction mixture was adjusted to pH 3 with dilute hydrochloric acid and extracted with ethyl acetate. The 15 extract was washed with saturated brine and the organic layer was dried with sodium sulfate. The solvent was distilled off under reduced pressure to give Z-N-Me-Val-N Me-Tyr(3-tBu)-OH. To a solution of this Z-N-Me-Val-N-Me Tyr(3-tBu)-OH in THF (20 ml), ethyl chloroformate (0.40 ml) 20 and NMM (0.46 ml) were added under cooling with ice and the mixture was stirred for 15 minutes. Subsequently, ammonia gas was bubbled into the reaction mixture for 5 minutes. The solvent was distilled off under reduced pressure and the precipitating salt was filtered off and washed with ethyl 25 acetate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent; n-hexane:ethyl acetate = 2:3) to give Z-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 in -147 7*'' 1.17 g (61%). (3) Synthesis of N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 A mixture of Z-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 (1.17 g) and 20% palladium hydroxide on carbon (0.24 g) in methanol 5 (20 ml) was stirred at room temperature in a hydrogen atmosphere for 1 hour. The reaction mixture was filtered and washed with methanol. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting 10 solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 100:10:1) to give N-Me-Val-N-Me-Tyr(3 tBu)-NH 2 in 609 mg (71%). (4) Synthesis of Z-Phe-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 To a solution of Z-Phe-OH (742 mg) in THF (3 ml), 15 isobutyl chloroformate (0.32 ml) and NMM (0.27 ml) were added under cooling with ice and the mixture was stirred for 15 minutes. Subsequently, a solution of N-Me-Val-N-Me Tyr(3-tBu)-NH 2 (600 mg) in THF (3 ml) was added and the mixture was stirred at room temperature for 10 hours. Water 20 was added to the reaction mixture and extraction was effected with ethyl acetate. The extract was washed with saturated brine, dried with sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; n 25 hexane:acetone = 3:2) to give Z-Phe-N-Me-Val-N-Me-Tyr(3 tBu)-NH 2 in 611 mg (58%). (5) Synthesis of Phe-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 A mixture of Z-Phe-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 -148 - (610 mg) and 10% palladium carbon (100 mg) in methanol (15 ml) was stirred at room temperature in a hydrogen atmosphere for 17 hours. The reaction mixture was filtered and washed with methanol. The solvent was distilled of f under reduced 5 pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate) to yield Phe-N-Me-Val-N-Me-Tyr(3-tBu)-NH 2 in 431 mg (89%). EI -MS: 511 (M*+1) NMR(method gCDCl 3 ): 0 0.50(9/10H,d,J=6.3Hz), 10 0.75(9/10H,d,J=6.6Hz), 0.79(21/10H,d,J=6.9Hz), 0.93(21/10H,d,J=6.6Hz), 1.34(63/10H,s), 1.39(27/10H,s), 2.15-2.99(46/10H,m), 2.46(21/10H,s), 2.78(21/10H,s), 3.02(9/10H,s), 3.03(9/10H,s), 3.15(7/10H,dd,J=14.9,5.9Hz), 3.33(3/10H,dd,J=13.9,6.9Hz), 3.72(7/10H,dd,J=8.9,5.OHz), 15 3.91(3/10H,dd,J=8.1,5.lHz), 4.92(3/10H,d,J=10.9Hz), 5.02 5.09(14/10H,m), 5.29(7/10H,brs), 5.49(7/10H,dd,J=10.7,5.8Hz), 5.98(7/10H,brs), 6.32(7/10H,d,J=7.9Hz), 6.60-6.67(6/10H,m), 6.72(7/10H,dd,J=7.9,2.OHz), 6.97(3/10H,dd,J=7.9,2.OHz), 7.10-7.39(67/10H,m) 20 Example 120 N-[2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-3-methyl 2-[N-methyl-N-(N-Me-phenylalaninoyl)amino]butanamide To a solution of 115 mg (0.359 mmol) of N-[2-(3-tert butyl-4-hydroxyphenyl)-1-methylethyl]-3-methyl-2 25 (methylamino)butanamide and 170 mg (0.610 mmol) of Boc-N-Me Phe-OH in methylene chloride (1.5 ml), 318 mg (0.718 mmol) of BOP and 0.10 ml (0.718 mmol) of TEA were added in succession under cooling with ice. After being stirred at - 149 room temperature for 2 days, the reaction mixture was diluted with methylene chloride and washed with water. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure; 5 the resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol = 150:1) to give N-[2-(3-tert-butyl-4-hydroxyphenyl)-1 methylethyl] -2- [N- (N-Boc-N-Me-phenylalaninoyl)

-N

methylamino]-3-methylbutanamide in 149 mg (71%). 10 A portion (145 mg) of the N-[2-(3-tert-butyl-4 hydroxyphenyl)-1-methylethyl]-2-[N-(N-Boc-N-Me-phenyl alaninoyl)-N-methylamino]-3-methylbutanamide was dissolved in methylene chloride (2 ml) and, after adding TFA (1 ml), the solution was stirred at room temperature for 15 minutes. 15 The solvent was distilled off under reduced pressure and the resulting residue was diluted with methylene chloride and washed with saturated aqueous NaHCO 3 . The resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous 20 ammonia at a ratio of 80:1:0.1) to yield N-[2-(3-tert-butyl 4-hydroxyphenyl) -1-methylethyl] -3-methyl-2- [N-methyl-N- (N Me-phenylalaninoyl)amino]butanamide in 86 mg (72%). EI-MS: 481(M ) NMR(method gCDCl 3 ): 8 0.52(1H,d,J=6.6Hz), 25 0.78(2H,d,J=6.6Hz), 0.93(3H,d,J=6.3Hz),1.08(lH,d,J=6.6Hz), 1.13(2H,d,J=6.6Hz), 1.36(5H,s), 1.39(4H,s), 2.1-2.3(lH,m), 2.25(2H,s), 2.32(lH,s), 2.5-2.9(3H,m), 2.59(2H,s), 2.62(1H,s), 3.08(1/2H,d,J=6.6Hz), 3.58(1/2H,t,J=6.3Hz), - 150 - 3.65-3.73(1/2H,m), 4.07-4.25(3/5H,m), 4.46(2/5H, d,J=11.2Hz), 5.62(1/2H,brs), 6.06(1/2H,d,J=8.3Hz), 6.59-6.64(lH,m), 6.75 6.94(lH,m), 7.01-7.12(lH,m), 7.2-7.4(6H,m), 8.18(1/2H,d,J=8.3Hz) 5 Example 121 N-[2-(3-tert-butyl-4-hydroxyphenyl)-1-methylethyl]-N-Me-3 methyl-2-(N-methyl-N-phenylalaninoylamino)butanamide (1) Synthesis of 2-(4-benzyloxy-3-tert-butylphenyl)-N (benzyloxycarbonyl)-N-Me-1-methylethylamine 10 To a solution in ethanol (18 ml) and THF (3 ml) of 1.60 g (3.27 mmol) of Z-N-Me-Phe(3-tBu-4-benzyloxy)-OMe prepared in accordance with Example 91, 4.9 ml (9.80 mmol) of a solution of 2 M lithium borohydride in THF was added under cooling with ice and the mixture was stirred overnight 15 at room temperature. After addition of water, the reaction mixture was extracted with ethyl acetate and the extract was washed with saturated brine, dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in methylene 20 chloride (15 ml); after adding 0.88 ml (6.32 mmol) of triethylamine and 0.27 ml (3.47 mmol) of methanesulfonyl chloride successively under cooling with ice, the solution was stirred for 30 minutes. The reaction mixture was washed with saturated aqueous NaHCO 3 and the organic layer was 25 dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane = 1:2) to give mesylate in - 151 - 0.88 g (50% in two steps). To a solution of the mesylate (0.88 g, 1.62 mmol) in THF (5 ml), 5.8 ml (5.8 mmol) of a solution of 1 M lithium triethylborohydride in THF was added. After stirring for 1.5 hours, water was added to the 5 reaction mixture under cooling with ice and it was then extracted with methylene chloride. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl 10 acetate:n-hexane = 1:5) to give 2-(4-benzyloxy-3-tert-butyl phenyl) -N- (benzyloxycarbonyl) -N-Me-i-methylethylamine in 0.50 g (68%). (2) Synthesis of 2-(3-tert-butyl-4-hydroxyphenyl)-N-Me-1 methylethylamine 15 A suspension of 0.49 g (1.09 mmol) of 2-(4-benzyloxy 3-tert-butyl-phenyl)-N-(benzyloxycarbonyl)-N-Me-1 methylethylamine and 0.10 g of a 20% palladium hydroxide on carbon catalyst in methanol (5 ml) was stirred in a hydrogen atmosphere for 2.5 hours. 'After filtering off the catalyst, 20 the solvent was distilled off under reduced pressure to give 2-(3-tert-butyl-4-hydroxyphenyl)-N-Me-1-methylethylamine in 0.23 g (96%). NMR(method g,CDCl 3 ): 8 1.12(3H,d,J=6.3Hz), 1.38(9H,s), 2.42(s, 3H), 2.64(2H,d,J=6.6Hz), 2.75-2.90(lH,m), 6.55(lH,dJ=7.9Hz), 25 6.84(1H,dd,J=1.6,7.9Hz), 7.04(1H,d,J=1.6Hz) (3) Synthesis of N-[2-(3-tert-butyl-4-hydroxyphenyl)-1 methylethyl]-N-Me-3-methyl-2-methylaminobutanamide To a solution of 0.22 g (0.994 mmol) of 2-(3-tert - 152 ii butyl-4-hydroxyphenyl)-N-Me-1-methylethylamine, 0.55 mg (2.09 mmol) of Z-N-Me-Val-OH and 0.30 g (1.99 mmol) of HOBT in DMF (3 ml), 0.31 ml (1.99 mmol) of DIC was added under cooling with ice. After being stirred at room temperature 5 for 38 hours, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO 3 , water and saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column 10 chromatography (eluting solvent; ethyl acetate:n-hexane = 1:4) to give 2- [N- (benzyloxycarbonyl) -N-methylamino] -N- [2 (3-tert-butyl-4-hydroxyphenyl) -1-methylethyll-N-Me-3 methylbutanamide in 155 mg (33%). A solution of 150 mg (0.320 mmol) of 2-[N-(benzyloxy 15 carbonyl)-N-methylamino]-N-[2-(3-tert-butyl-4 hydroxyphenyl) -1-methylethyl] -N-Me- 3 -methylbutanamide and 0.02 g of a 20% palladium hydroxide on carbon catalyst in methanol (2 ml) was stirred in a hydrogen atmosphere for 3 hours. After filtering off the catalyst, the solvent was 20 distilled off under reduced pressure to give N-[2-(3-tert butyl-4-hydroxyphenyl) -1-methylethyl] -N-Me-3-methyl-2 (methylamino)butanamide in 97 mg (92%). (4) Synthesis-of N-[2-(3-tert-butyl-4-hydroxyphenyl)-1 methylethyl]-N-Me-3-methyl-2-(N-methyl-N-phenhlalaninoyl 25 amino)butanamide To a solution of 93 mg (0.278 mmol) of N-[2-(3-tert butyl-4-hydroxyphenyl)-1-methylethyl]-N-Me-3-methyl-2 (methylamino)butanamide and 125 mg (0.473 mmol) of Boc-Phe - 153 - OH in methylene chloride (1.5 ml), 246 mg (0.556 mmol) of BOP and 0.077 ml (0.556 mmol) of TEA were successively added under cooling with ice. After being stirred at room temperature for 2.5 days, the reaction mixture was diluted 5 with methylene chloride and washed with water. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol = 150:1) to give N-[2-(3-tert 10 butyl-4-hydroxyphenyl)-1-methylethyl]-2-[N-(N-Boc-phenyl alaninoyl)-N-methylamino]-N-Me-3-methylbutanamide in 108 mg (67%). The thus obtained N-[2-(3-tert-butyl-4-hydroxyphenyl) 1-methylethyl]-2-[N-(N-Boc-phenylalaninoyl)-N-methylamino] 15 N-Me-3-methylbutanamide (108 mg) was dissolved in methylene chloride (2 ml) and, after adding TFA (1 ml), the solution was stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure and the resulting residue was diluted with methylene chloride and washed with 20 saturated aqueous NaHCO 3 . The resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 60:1:0.1) to yield N-[2-(3-tert-butyl 4-hydroxyphenyl) -1-methylethyl] -N-Me-3-methyl-2- (N-methyl-N 25 phenylalaninoylamino)butanamide in 71 mg (80%). EI-MS: 481(M*) NMR(method gCDCl 3 ): 8 0.41(3H,d,J=6.6Hz), 0.74(3H,d,J=6.6Hz), 1.08(3H,d,J=6.6Hz), 1.36(9H,s), - 154 - 2.07-2.24(lH,m), 2.55-2.76(2H,m), 2.81(3H,s), 2.86-3.00(2H,m), 2.90(3H,s), 3.94(1H,t,J=6.6Hz), 4.94(1H,d,J=10.9Hz), 5.02-5.11(lH,m), 6.61(1H,d,J=8.3Hz), 6.89(1H,dd,J=2.0,7.9Hz), 7.00(1H,d,J=1.7Hz), 7.10-7.35(6H,m) 5 Test 1 Motilin receptor binding test A motilin receptor binding test was conducted in the following manner [Bormans et al., Regul. Peptides, 15, 143 (1986)]. The duodenum was extracted from a slaughtered 10 rabbit, had the mucous membrane separated and homogenized in 50 mM Tris-HCl buffer to prepare a receptor sample. The sample was incubated together with 1251 motilin 25 pM and thereafter the radioactivity bound to the receptor was measured. Specific binding was defined as the difference 15 between the radioactivity in the case of no adding and that in the case of adding a great excess amount of motilin (10~ 7 M). The activity of the drug was expressed by ICO (in nM), as the concentration sufficient to reduce the specific binding by 50%. The results are shown in Table C-1. 20 Test 2 Action on the contraction of a specimen of longitudinal muscle in the duodenum extracted from a rabbit The action on the motilin-induced contraction of a specimen of longitudinal muscle in the duodenum extracted 25 from a rabbit was investigated by the following method. A duodenum specimen extracted from a slaughtered rabbit (3 x 10 mm) was suspended in an organ bath (10 ml) such that the longitudinal muscle would run vertically; the bath was -155 UAJ filled with a Krebs solution kept at 28 0 C. A mixed gas (95% 02 and 5% CO 2 ) was continuously bubbled into the Krebs solution and the contraction of the duodenum specimen was recorded isotonically (with a 1-g load) via an isotonic 5 transducer (TD-111T of Nihon Koden, K.K.) The degree of contraction was expressed in relative values, with the contraction by acetylcholine at a dose of 10~ 4 M being taken as 100%. The activity of the drug was calculated as pA 2 value indicating its effect on the dose-dependent muscle 10 contraction by the motilin put into the organ bath. The results are shown in Table C-1. Table C-1 Motilin receptor Contraction Example No. binding test, ICO (nM) suppressing test, pA 2 5 12 7.81 18B 3.7 8.58 118 1.9 8.43 119 4.3 8.59 15 Industrial Applicability The compounds of the invention typically function as a motilin receptor antagonist and are useful as medicines including therapeutics of irritable bowel syndrome. - 156 -

Claims (13)

1. A compound represented by the general formula (1), a hydrate thereof or a pharmaceutically acceptable salt thereof: R5 R4 (1) R 1 -A'N R 3 (wherein A is an amino acid residue or an Na-substituted amino acid residue, provided that A binds with -NR 2 - to form an amide; Rl is an optionally substituted straight-chained or branched alkyl group having 2 - 7 carbon atoms, an optionally substituted straight-chained or branched alkenyl group having 3 - 8 carbon atoms, or an optionally substituted straight-chained or branched alkynyl group having 3 - 8 carbon atoms; R 2 is a hydrogen atom or an optionally substituted straight-chained or branched alkyl group having 1 - 3 carbon atoms; R 3 is -CO-R 7 , an optionally substituted straight chained or branched alkyl group having 1 - 5 carbon atoms, an optionally substituted straight-chained or branched alkenyl group having 2 - 5 carbon atoms or an optionally substituted straight-chained or branched alkynyl group having 2 - 5 carbon atoms; R 4 is a hydrogen atom, a straight-chained or branched - 157 - alkyl group having 1 - 6 carbon atoms, a straight-chained or branched alkenyl group having 2 - 6 carbon atoms, a straight-chained or branched alkynyl group having 2 - 6 carbon atoms, or the general formula (2): R 16 (2) R 17 R, is a hydrogen atom or -OR.; R 6 is an optionally substituted straight-chained or branched alkyl group having 1 - 6 carbon atoms, an optionally substituted straight-chained or branched alkenyl group having 2 - 7 carbon atoms, an optionally substituted alkynyl group having 2 - 7 carbon atoms, a cycloalkyl group having 3 - 7 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, an optionally substituted aromatic ring having 6 - 12 carbon atoms, an optionally substituted saturated or unsaturated heterocyclic ring having 3 - 12 carbon atoms, -N(R,)Rlo or -OR,,; R 7 is a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon atoms, a cycloalkyl group having 3 - 7 carbon atoms, N(R 12 )R. 3 or -OR 1 4 ; R 8 is a hydrogen atom or a straight-chained alKyl group having 1 - 4 carbon atoms; R 9 and Rio, which may be the same or different, each represent a hydrogen atom, an optionally substituted - 158 - straight-chained or branched alkyl group having 1 - 5 carbon atoms, an optionally substituted straight-chained or branched alkenyl group having 2 - 6 carbon atoms, an optionally substituted straight-chained or branched alkynyl group having 2 - 6 carbon atoms, a cycloalkyl group having 3 - 6 carbon atoms that may be fused to'a benzene ring or a heterocyclic ring, or an optionally substituted aromatic ring having 6 - 12 carbon atoms; R 11 is an optionally substituted straight-chained or branched alkyl group having 1 - 5 carbon atoms, an optionally substituted straight-chained branched alkenyl group having 2 - 6 carbon atoms, an optionally substituted straight-chained or branched alkynyl group having 2 - 6 carbon atoms, a cycloalkyl group having 3 - 6 carbon atoms that may be fused to a benzene ring or a heterocyclic ring, or an optionally substituted aromatic ring having 6 - 12 carbon atoms; R 12 and R 13 , which may be the same or different, each represent a hydrogen atom, a straight-chained or branched alkyl group having 1 - 4 carbon atoms or a cycloalkyl group having 3 - 7 carbon atoms; R 14 is a hydrogen atom, a straight-chained or branched alkyl group having 1 - 6 carbon atoms, or a cycloalkyl group having 3 - 7 carbon atoms; R 15 is a hydrogen atom or a methyl group; R 16 and Rl 7 , when taken together, represent a cycloalkyl or cycloalkenyl group having 3 - 7 carbon atoms).

2. The compound according to claim 1, a hydrate thereof - 159 or a pharmaceutically acceptable salt thereof, wherein A in the general formula (1) is valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), phenylglycine (Phg), hydroxyproline (Hyp), homophenylalanine (Hph), cyclohexylglycine (Chg), cyclohexylalanine (Cha), tert-leucine (Tle), 2 thienylalanine (Thi), N-methylvaline (N-Me-Val), N methylleucine (N-Me-Leu), N-methylisoleucine (N-Me-Ile), N methylphenylalanine (N-Me-Phe), N-methylphenylglycine (N-Me Phg), N-methylcyclohexylalanine (N-Me-Cha) or N-methyl-tert leucine (N-Me-Tle).

3. The compound according to any one of claims 1 and 2, a hydrate thereof or a pharmaceutically acceptable salt thereof, wherein R 1 in the general formula (1) is a phenylalaninoyl group, a N-Me-phenylalaninoyl group, a [-(3 indolyl)alaninoyi group, a tyrosinoyl group, a -(2 thienyl)alaninoyl group, a -(2-furyl)alaninoyl group, a 3 cyclohexylalaninoyl group, a 3-phenylbutyryl group, a 1 benzocyclobutylcarbonyl group, a benzylaminocarbonyl group or a benzyloxycarbonyl group.

4. The compound according to any one of claims 1 - 3, a hydrate thereof or a pharmaceutically acceptable salt thereof, wherein R 2 in the general formula (1) is a hydrogen atom or a methyl group.

5. The compound according to any one of claims 1 - 4, a hydrate thereof or a pharmaceutically acceptable salt thereof, wherein R 3 in the general formula (1) is an amido group, an - 160 - N-methylamido group, a methyl group or an aminomethyl group.

6. The compound according to any one of claims 1 - 5, a hydrate thereof or a pharmaceutically acceptable salt thereof, wherein R 4 in the general formula (1) is an isopropyl group, a tert-butyl group (tBu), a 1,1-dimethylpropyl group or a 1,1-dimethyl-2-propenyl group.

7. The compound according to any one of claims 1 - 6, a hydrate thereof or a pharmaceutically acceptable salt thereof, wherein R 5 in the general formula (1) is a hydroxyl group or a methoxy group.

8. The compound according to claim 1, a hydrate thereof or a pharmaceutically acceptable salt thereof, wherein A in the general formula (1) is valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), phenylglycine (Phg), hydroxyproline (Hyp), homophenylalanine (Hph), cyclohexylglycine (Chg), cyclohexylalanine (Cha), tert-leucine (Tle), 2 thienylalanine (Thi), N-methylvaline (N-Me-Val), N methylleucine (N-Me-Leu), N-methylisoleucine (N-Me-Ile), N methylphenylalanine (N-Me-Phe), N-methylphenylglycine (N-Me Phg), N-methylcyclohexylalanine (N-Me-Cha) or N-methyl-tert leucine (N-Me-Tle); R 1 is a phenylalaninoyl group, a N-Me phenylalaninoyl group, a P-(3-indolyl)alaninoyl group, a tyrosinbyl group, a P-(2-thienyl)alaninoyl group, a -(2 furyl)alaninoyl group, a P-cyclohexylalaninoyl group, a 3 phenylbutyryl group, a 1-benzocyclobutylcarbonyl group, a benzylaminocarbonyl group or a benzyldxycarbonyl group; R 2 - 161 - is a hydrogen atom or a methyl group; R, is an amido group, an N-methylamido group, a methyl group or an aminomethyl group; R 4 is an isopropyl group, a tert-butyl group (tBu), a 1,1-dimethylpropyl group or a 1,1-dimethyl-2-propenyl group; and R. is a hydroxyl group or a methoxy group.

9. The compound according to claim 1, a hydrate thereof or a pharmaceutically acceptable salt thereof which are selected from the group of compounds consisting of Phe-Phg Tyr(3-tBu)-NH 2 , Phe-N-Me-D-Phg-Tyr(3-tBu)-NH 2 , Phe-Phe Tyr(3-tBu)-NH 2 , Phe-Cha-Tyr(3-tBu)-NH 2 , Phe-Val-Tyr(3-tBu) NH 2 , Phe-Leu-Tyr(3-tBu)-NH 2 , Phe-Tyr-Tyr(3-tBu)-NH 2 , Phe-Hph Tyr(3-tBu)-NH 2 , Phe-Ile-Tyr(3-tBu)-NH 2 , Trp-Phg-Tyr(3-tBu) NH 2 , Cha-Phg-Tyr(3-tBu)-NH 2 , Phe-Val-N-Me-Tyr(3-tBu)-NH 2 , Phe-Phg-Tyr(3-tBu)-NHMe, N-(benzylaminocarbonyl)-N-Me-D-Phe Tyr(3-tBu)-NH 2 , N-(S)-3-phenylbutyryl-Phg-Tyr(3-tBu)-NH 2 , N (2-amino-3-phenylpropyl)-Phg-Tyr(3-tBu)-NH 2 , N-(2-amino-3 phenylpropyl)-Val-Tyr(3-tBu)-NH 2 , N-[2-(3-tert-butyl-4 hydroxyphenyl)-1-methylethyl]-3-methyl-2-(N-methyl-N phenylalaninoylamino)butanamide, Phe-N-Me-Val-N-Me-Tyr(3 tBu)-NH 2 , and N-[2-(3-tert-butyl-4-hydroxyphenyl)-1 methylethyl]-3-methyl-2-[N-methyl-N-(N-Me-phenyl alaninoyl)amino]butanamide.

10. A medicine containing the compound according to any one of claims 1 - 9 as an active ingredient.

11. A motilin receptor antagonist containing the compound according to any one of claims 1 - 9.

12. A gastrointestinal motility suppressor containing the compound according to any one of claims 1 - 9 as an active - 162 - ingredient.

13. A therapeutic of hypermotilinemia containing the compound according to any one of claims 1 - 9 as an active ingredient. - 163 -